Fused heterocyclic compound

ABSTRACT

[wherein each symbol is as defined herein.].

TECHNICAL FIELD

The present invention relates to a novel compound having an inhibitoryaction against cdc2-like kinase (cdc2-like kinase; hereinafter sometimesabbreviated as CLK), or a salt thereof. The present invention alsorelates to a medicament which contains the compound or salt thereof andwhich is used for preventing or treating a CLK-related disease such ascancer.

BACKGROUND ART

Abnormal control of an alternative splicing mechanism has been reportedin various diseases such as neurodegenerative disease, amyotrophiclateral sclerosis and cancer. Particularly in cancer, cancer-specificsplicing variants produced by abnormal alternative splicing have beenshown to play an important role in cancer survival and invasion. Inrecent years, it has been shown that spliceosome constituent factorssuch as SF3B1, SRSF2 and U2AF 1 are mutated with high frequency in theosteomyelodysplasia syndrome. These findings indicate that control of analternative splicing mechanism plays an important role in cancer.

CLK family kinase is a type of bispecific protein kinase retaining bothserine/threonine kinase activity and tyrosine kinase activity, andinclude four types of kinase: CLK1 to CLK4. CLK phosphorylates SRproteins such as SRSF1 to control localization of the proteins, so thata splicing regulation mechanism by SR proteins is controlled. It hasbeen shown that by regulating alternative splicing by inhibition of CLKkinase activity, signals essential for survival of cancer can behindered to inhibit growth of cancer cells. In addition, CLK2 has beenshown to act as an oncogene in breast cancer. Therefore, inhibition ofkinase activity of CLK may be a promising treatment for cancer.

Patent Literatures 1 and 2 disclose a fused heterocyclic compound as acompound having a tyrosine kinase inhibitory action. Patent Literatures3 and 4 disclose a fused heterocyclic compound having otherpharmacological activities.

CITATION LIST Patent Literature

PATENT LITERATURE 1: WO 00/71129

PATENT LITERATURE 2: WO 2004/009784

PATENT LITERATURE 3: WO 2014/143610

PATENT LITERATURE 4: WO 2012/003576

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a compound which has anexcellent CLK inhibitory action, and is satisfactory as a pharmaceuticalproduct.

Solution to Problem

The present inventors have found that a compound represented by thefollowing formula or a salt thereof has excellent CLK inhibitoryactivity, and is useful for prevention and treatment of cancer and thelike. On the basis of this finding, the present inventors have conductedintensive studies, leading to completion of the present invention. Thatis, the present invention is as follows.

[1] A compound represented by formula (I), or

a salt thereof (herein sometimes abbreviated as “compound (I)”):

[wherein

R¹ represents a substituent or a hydrogen atom;

R² represents an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group;

R⁶ and R⁷ each independently represent a hydrogen atom, a halogen atomor an optionally substituted hydrocarbon group; and

ring A represents a bicyclic aromatic heterocyclic ring selected fromthe following formulas (1), (2), (3), (4) and (5):

wherein Xs each independently represent N or C(R⁵); and

R³, R⁴ and R⁵ each independently represent a hydrogen atom or asubstituent.].

[2] The compound or salt thereof according to [1], wherein

R² is

(I) a C₁₋₆ alkyl group optionally having 1 to 3 five- or six-memberedmonocyclic aromatic heterocyclic groups optionally having 1 to 3optionally halogenated C₁₋₆ alkyl groups; or

(II) an optionally halogenated C₇₋₁₆ aralkyl group.

[3] The compound or salt thereof according to [1], wherein ring A is abicyclic aromatic heterocyclic ring represented by the following formula(1).

[4] The compound or salt thereof according to [1], wherein R³ is ahydrogen atom;

R⁴ is (a) an amino group optionally monosubstituted or disubstitutedwith a C₁₋₆ alkyl group, or

(b) a C₁₋₆ alkoxy group; and

R⁵ is (a) a C₁₋₆ alkoxy group, or

(b) a C₁₋₆ alkyl group optionally having 1 to 3 hydroxy groups.

[5] The compound or salt thereof according to [1], wherein R¹ is

(I) a C₁₋₆ alkyl group optionally having 1 to 5 substituents eachselected from

(a) a halogen atom,

(b) a hydroxy group,

(c) a cyano group,

(d) a C₁₋₆ alkoxy group optionally having 1 to 3 substituents eachselected from

(i) a halogen atom, and

(ii) a hydroxy group, and

(e) a three- to eight-membered nonaromatic heterocyclic group having 1to 3 halogen atoms;

(II) a three- to eight-membered nonaromatic heterocyclic groupoptionally having 1 to 5 substituents each selected from

(a) a C₁₋₆ alkoxy group,

(b) a halogen atom, and

(c) a hydroxy group;

(III) a five- to fourteen-membered aromatic heterocyclic groupoptionally having 1 to 3 optionally halogenated C₁₋₆ alkyl groups;

(IV) a C₁₋₆ alkoxy group optionally having 1 to 5 substituents eachselected from

(a) a hydroxy group,

(b) a three- to eight-membered nonaromatic heterocyclic group, and

(c) a five- or six-membered monocyclic aromatic heterocyclic groupoptionally having 1 to 3 optionally halogenated C₁₋₆ alkyl groups;

(V) an optionally halogenated C₃₋₁₀ cycloalkyl group; or

(VI) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group optionally having 1 to 5 substituents each selectedfrom

(a) (i) halogen atom,

(ii) a hydroxy group, and

(iii) C₁₋₆ alkoxy group;

R² is

(I) a C₁₋₆ alkyl group optionally having 1 to 3 five- tofourteen-membered aromatic heterocyclic groups optionally having 1 to 3substituents each selected from

(a) a halogen atom,

(b) a C₁₋₆ alkyl group optionally having 1 to 7 substituents eachselected from

(i) a halogen atom,

(ii) a hydroxy group, and

(iii) a C₁₋₆ alkoxy group,

(c) an optionally halogenated C₃₋₁₀ cycloalkyl group,

(d) a C₁₋₆ alkoxy group,

(e) a C₁₋₆ alkyl group-C₃₋₁₀ cycloalkyl group,

(f) a C₁₋₆ alkyl group-three- to eight-membered monocyclic nonaromaticheterocyclic group, and

(g) an oxo group; or

(II) a C₇₋₁₆ aralkyl group optionally having 1 to 3 substituents eachselected from

(a) a C₁₋₆ alkyl group optionally having 1 to 3 substituents eachselected from

(i) a halogen atom, and

(ii) a hydroxyl group,

(b) a C₁₋₆ alkoxy-carbonyl group,

(c) a halogen atom,

(d) a C₁₋₆ alkoxy group optionally having 1 to 3 substituents eachselected from

(i) a halogen atom, and

(ii) a hydroxyl group

(e) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(f) a cyano group,

(g) an amino group optionally monosubstituted or disubstituted with asubstituent selected from

(i) a C₁₋₆ alkyl group, and

(ii) a C₁₋₆ alkoxy-carbonyl group,

(h) a nitro group, and

(i) a carboxy group;

each of R⁶ and R⁷ is a hydrogen atom;

ring A is a bicyclic aromatic heterocyclic ring selected from theformulas (1), (2), (3) and (4);

Xs each independently represents C(R⁵) or N;

R³ is a hydrogen atom;

R⁴ is

(I) a hydrogen atom,

(II) a halogen atom,

(III) an optionally halogenated C₁₋₆ alkoxy group, or

(IV) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group; and

R⁵ is

(I) a hydrogen atom,

(II) a halogen atom,

(III) a cyano group,

(IV) a C₁₋₆ alkyl group optionally having 1 to 5 substituents eachselected from

(a) a halogen atom,

(b) a C₁₋₆ alkoxy group,

(c) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,

(d) a hydroxy group, and

(e) a C₁₋₆ alkyl-carbonyloxy group,

(V) a C₁₋₆ alkoxy group,

(VI) a C₂₋₆ alkenyl group optionally having 1 to 3 C₁₋₆ alkoxy groups,

(VII) a C₂₋₆ alkynyl group,

(VIII) a cyano-C₆₋₁₄ aryl group,

(IX) a five- to fourteen-membered aromatic heterocyclic group optionallyhaving 1 or 2 C₁₋₆ alkyl groups optionally having 1 to 3 substituentseach selected from

(a) a halogen atom,

(b) a five- or six-membered monocyclic aromatic heterocyclic group, and

(c) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup,

(X) a C₁₋₆ alkyl-carbonyl group,

(XI) a hydroxy group,

(XII) a C₁₋₆ alkyl-five- to fourteen-membered aromatic heterocyclic oxygroup,

(XIII) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup optionally having 1 to 3 substituents each selected from

(a) a halogen atom,

(b) a C₁₋₆ alkoxy group, and

(c) an oxo group, or

(XIV) an amino group optionally monosubstituted or disubstituted with anoptionally halogenated C₁₋₆ alkyl.

[6]6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine,or a salt thereof.

[7]1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine,or a salt thereof.

[8]1-((5-(1,1-difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine,or a salt thereof.

[9]1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine,or a salt thereof.

[10] A medicament including the compound or salt thereof according to[1].

[11] The medicament according to [10] which is a CLK inhibitor.

[12] The medicament according to [10] which is a prophylactic ortherapeutic agent for cancer.

[13] A method for inhibiting CLK in a mammal, including administering tothe mammal an effective amount of the compound or salt thereof accordingto [1].

[14] A method for preventing or treating cancer in a mammal, includingadministering to the mammal an effective amount of the compound or saltthereof according to [1].

[15] The compound or salt thereof according to [1] for use in preventionand treatment of cancer.

[16] Use of the compound or salt thereof according to [1] for producinga prophylactic or therapeutic agent for cancer.

Advantageous Effects of Invention

The compound (I) has an excellent CLK inhibitory action, and is usefulfor prevention and treatment of cancer and the like.

DESCRIPTION OF EMBODIMENTS

Hereinafter, compounds of the present invention, methods for productionthereof, and uses of thereof will be described in detail.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl. In the present specification, examples of the “C₂₋₆ alkynylgroup” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl. Inthe present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[substituent group A](1) a halogen atom,(2) a nitro group,(3) a cyano group,(4) an oxo group,(5) a hydroxy group,(6) an optionally halogenated C₁₋₆ alkoxy group,(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethyl sulfonyloxy),(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),(20) an optionally halogenated C₁₋₆ alkylthio group,(21) a 5- to 14-membered aromatic heterocyclic group,(22) a 3- to 14-membered non-aromatic heterocyclic group,(23) a formyl group,(24) a carboxy group,(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,(26) a C₆₋₁₄ aryl-carbonyl group,(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,(29) a C₁₋₆ alkoxy-carbonyl group,(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),(32) a carbamoyl group,(33) a thiocarbamoyl group,(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,(39) a C₆₋₁₄ arylsulfonyl group,(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),(44) an amino group,(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),(49) a formylamino group,(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),(51) a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),(53) a C₁₋₆ alkoxy-carbonyl amino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),(55) a C₁₋₆ alkylsulfonylamino group (e.g., methyl sulfonylamino, ethylsulfonylamino),(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenyl sulfonylamino, toluenesulfonylamino),(57) an optionally halogenated C₁₋₆ alkyl group,(58) a C₂₋₆ alkenyl group,(59) a C₂₋₆ alkynyl group,(60) a C₃₋₁₀ cycloalkyl group,(61) a C₃₋₁₀ cycloalkenyl group and(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonyl amino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl)(C₆₋₁₄ aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆-14aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₁₋₆ alkylene group”include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH(C₃H₇)—, —CH(CH(CH₃)₂)—,—(CH(CH₃))₂—, —CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(CH₃)₂— and —C(CH₃)₂—CH₂—CH₂—CH₂—.

In the present specification, examples of the “C₂₋₆ alkenylene group”include —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—,—CH═CH—C(CH₃)₂—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH═CH—.

In the present specification, examples of the “C₂₋₆ alkynylene group”include —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—,—CH₂—C≡C—CH₂—, —CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—,—C≡C—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—C≡C—.

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and

8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocycles such as benzothiophene, benzofuran, benzimidazole,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole,benzotriazole, imidazopyridine, thienopyridine, furopyridine,pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine,imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine,pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine,thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine,naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole,purine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and thelike.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include a “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, “a group via a carbon atom” means a grouphaving an atomic bonding on the carbon atom; examples include a cyanogroup, a hydrocarbon group optionally having substituent(s), an acylgroup, an optionally esterified carboxyl group, an imidoyl groupoptionally having substituent(s), an amidino group optionally havingsubstituent(s), a carbamoyl group optionally having substituent(s), athiocarbamoyl group optionally having substituent(s), a heterocyclicgroup via a carbon atom, optionally having substituent(s), etc.

Examples of “a heterocyclic group via a carbon atom” in the “aheterocyclic group via a carbon atom, optionally having substituent(s)”include a heterocyclic group having an atomic bonding on the carbon atomin the “heterocyclic group”.

Examples of “an acyl group via a carbon atom” include an acyl grouphaving an atomic bonding on the carbon atom in the “acyl group”;examples include a formyl group, a carboxyl group, a carbamoyl group, athiocarbamoyl group, etc, each optionally having “1 or 2 substituentsselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄ aryl group, aC₇₋₁₆ aralkyl group, a 5- to 14-membered aromatic heterocyclic group anda 3- to 14-membered non-aromatic heterocyclic group, each of whichoptionally has 1 to 3 substituents selected from a halogen atom, anoptionally halogenated C₁₋₆ alkoxy group, a hydroxy group, a nitrogroup, a cyano group, an amino group and a carbamoyl group”.

In the present specification, “a group via a nitrogen atom” means agroup having an atomic bonding on the nitrogen atom; examples includeheterocyclic groups via a nitrogen atom (1) a nitro group, (2) an aminogroup optionally having 1 or 2 of the above described “a group via acarbon atom”, (3) an amino group optionally having 1 or 2 “a group via anitrogen atom”, (4) a heterocyclic group via a nitrogen atom, optionallyhaving a substituent.

In the present specification, “a group via an oxygen atom” means a grouphaving an atomic bonding on the oxygen atom; examples include a hydroxygroup optionally having one “group via a carbon atom” described above.

In the present specification, “a group via a sulfur atom” means a grouphaving an atomic bonding on the sulfur atom; examples include a sulfanylgroup optionally having one “group via a carbon atom” or “group via anitrogen atom” described above, optionally being oxidized.

Hereinafter, the definition of each symbol in the formula (I) will bedescribed in detail.

R¹ is preferably a substituent selected from

(I) a C₁₋₆ alkyl group (particularly methyl or ethyl) optionally having1 to 5 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a hydroxy group,

(c) a cyano group,

(d) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 3 substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxy group, and

(e) a three- to eight-membered nonaromatic heterocyclic group(particularly azetidinyl) having 1 to 3 halogen atoms (particularlyfluorine atoms);

(II) a three- to eight-membered nonaromatic heterocyclic group(particularly azetidinyl or pyrrolidinyl) optionally having 1 to 5(particularly 1 or 2) substituents each selected from

(a) a C₁₋₆ alkoxy group (particularly methoxy)

(b) a halogen atom (particularly fluorine), and

(c) a hydroxy group;

(III) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl or oxazolyl)) optionally having 1 to 3(particularly 1) optionally halogenated C₁₋₆ alkyl groups (particularlymethyl or difluoromethyl);

(IV) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 5 (particularly 1) substituents each selected from

(a) a hydroxy group,

(b) a three- to eight-membered nonaromatic heterocyclic group(particularly tetrahydrofuranyl), and

(c) a five- or six-membered monocyclic aromatic heterocyclic groupoptionally having 1 to 3 (particularly 1) optionally halogenated C₁₋₆alkyl groups (particularly methyl or difluoromethyl);

(V) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularlycyclopropyl or difluorocyclobutyl); and

(VI) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl, ethyl or isobutyl) optionallyhaving 1 to 5 (particularly 1 to 3) substituents each selected from

(a) (i) a halogen atom (particularly fluorine atom),

(ii) a hydroxy group, and

(iii) a C₁₋₆ alkoxy group (particularly methoxy).

R¹ is more preferably a substituent selected from

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3substituents each selected from

(a) a C₁₋₆ alkoxy group (particularly methoxy) and

(b) a hydroxy group;

(II) a three- to fourteen-membered nonaromatic heterocyclic group(particularly azetidinyl);

(III) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy); and

(IV) an amino group.

R¹ is a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) hydroxy groups.

R² is preferably

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(particularly 1) five- to fourteen-membered aromatic heterocyclic groups(particularly five- or six-membered monocyclic aromatic heterocyclicgroups (preferably oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl), isoxazolyl, isothiazolyl,thiazolyl, triazolyl (preferably 1,2,3-triazolyl or 1,2,4-triazolyl),pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, oxazolyl or furyl))optionally having 1 to 3 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine or chlorine),

(b) a C₁₋₆ alkyl group (particularly methyl, ethyl, isobutyl, isopropylor propyl) optionally having 1 to 7 (particularly 1 to 5) substituentseach selected from

(i) a halogen atom (particularly fluorine atom),

(ii) a hydroxy group, and

(iii) a C₁₋₆ alkoxy group (particularly methoxy),

(c) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularly,2,2-difluorocyclopropyl, cyclobutyl, cyclopropyl or difluorocyclobutyl(particularly 3,3-difluorocyclobutyl), fluorocyclobutyl (particularly1-fluorocyclobutyl), fluorocyclopropyl),

(d) a C₁₋₆ alkoxy group (particularly methoxy),

(e) a C₁₋₆ alkyl group-C₃₋₁₀ cycloalkyl group (particularlymethyl-cyclopropyl),

(f) a C₁₋₆ alkyl group-three- to eight-membered monocyclic nonaromaticheterocyclic group (particularly methyl-oxetanyl), and

(g) oxo group; or

(II) a C₇₋₁₆ aralkyl group (particularly benzyl) optionally having 1 to3 substituents each selected from

(a) a C₁₋₆ alkyl group (methyl or isopropyl) optionally having 1 to 3substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxyl group,

(b) a C₁₋₆ alkoxy-carbonyl group (particularly methoxycarbonyl),

(c) a halogen atom (fluorine or chlorine)

(d) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 3 substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxyl group

(e) a mono- or di-C₁₋₆ alkyl-carbamoyl group (particularlymethylcarbamoyl),

(f) a cyano group,

(g) an amino group optionally monosubstituted or disubstituted(particularly monosubstituted) with a substituent selected from

(i) a C₁₋₆ alkyl group, and

(ii) a C₁₋₆ alkoxy-carbonyl group (particularly tert-butoxy-carbonyl),

(h) a nitro group, and

(i) a carboxy group.

R² is more preferably

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) five- or six-membered monocyclic aromatic heterocyclicgroups (particularly oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl), isoxazolyl, thiazolyl,triazolyl (preferably 1,2,3-triazolyl or 1,2,4-triazolyl), pyrazinyl,pyrazolyl, pyridyl, pyrimidinyl or oxazolyl) optionally having 1 to 3(preferably 1) substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) an optionally halogenated C₁₋₆ alkyl group (particularly methyl,difluoromethyl, trifluoromethyl, ethyl, difluoroethyl (particularly1,1-difluoroethyl), 2,2,2-trifluoroethyl, isopropyl, 1-fluoroisopropylor 1-fluoroethyl), and

(c) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularly,2,2-difluorocyclopropyl, cyclobutyl, cyclopropyl or difluorocyclobutyl(particularly 3,3-difluorocyclobutyl), fluorocyclobutyl (particularly1-fluorocyclobutyl), fluorocyclopropyl); or

(II) a C₇₋₁₆ aralkyl group (particularly benzyl) optionally having 1 to3 (preferably 1 or 2) substituents each selected from

(a) a halogen atom (particularly fluorine or chlorine)

(b) an optionally halogenated C₁₋₆ alkyl group (particularlytrifluoromethyl), and

(c) an optionally halogenated C₁₋₆ alkoxy group (particularlydifluoromethoxy or trifluoromethoxy).

R² is still more preferably

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) five- or six-membered monocyclic aromatic heterocyclicgroups (particularly oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl),isoxazolyl) optionally having 1 to 3 (preferably 1) optionallyhalogenated C₁₋₆ alkyl groups (particularly methyl, difluoromethyl,difluoroethyl, fluoroisopropyl or fluoroethyl); or

(II) an optionally halogenated C₇₋₁₆ aralkyl (particularlydifluorobenzyl (preferably 3,5-difluorobenzyl)).

R² is even more preferably

a C₁₋₆ alkyl group (particularly methyl) having 1 to 3 (preferably 1)five- or six-membered monocyclic aromatic heterocyclic groups(particularly oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl),isoxazolyl) having 1 to 3 (preferably 1) halogenated C₁₋₆ alkyl groups(particularly methyl, difluoromethyl, difluoroethyl, fluoroisopropyl orfluoroethyl).

R⁶ is preferably a hydrogen atom.

R⁷ is preferably a hydrogen atom.

R⁶ and R⁷ are preferably each a hydrogen atom.

Ring A is preferably a bicyclic aromatic heterocyclic ring selected fromthe formulas (1), (2), (3) and (4).

Ring A is more preferably a bicyclic aromatic heterocyclic ringrepresented by the formula (1).

As preferable examples of R³, R⁴ and R⁵, in particular,

R³ is a hydrogen atom;

R⁴ is (I) a hydrogen atom,

(II) a halogen atom (particularly chlorine atom),

(III) an optionally halogenated C₁₋₆ alkoxy group (particularly methoxy,fluoromethoxy, difluoromethoxy or ethoxy), or

(IV) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl);

R⁵ is (I) a hydrogen atom,

(II) a halogen atom (particularly chlorine),

(III) a cyano group,

(IV) a C₁₋₆ alkyl group (particularly methyl, ethyl or isopropyl)optionally having 1 to 5 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy),

(c) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group, and

(e) a C₁₋₆ alkyl-carbonyloxy group (particularly,2,2-dimethylpropanoyloxy),

(V) a C₁₋₆ alkoxy group (particularly methoxy),

(VI) a C₂₋₆ alkenyl group (particular 1-propenyl or ethenyl) optionallyhaving 1 to 3 (particularly 1) C₁₋₆ alkoxy groups (particularlymethoxy),

(VII) a C₂₋₆ alkynyl group (particularly ethynyl),

(VIII) a cyano-C₆₋₁₄ aryl group (particularly cyano-phenyl),

(IX) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl, isoxazolyl or pyridyl)) optionally having 1or 2 C₁₋₆ alkyl groups (particularly methyl or ethyl) optionally having1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a five- to six-membered monocyclic aromatic heterocyclic group(particularly pyridyl), and

(c) a three- to eight-membered monocyclic nonaromatic heterocyclic group(particularly morpholinyl),

(X) a C₁₋₆ alkyl-carbonyl group (particularly acetyl),

(XI) a hydroxy group,

(XII) a C₁₋₆ alkyl-five- to fourteen-membered aromatic heterocyclic oxygroup (particularly methylpyrazolyloxy),

(XIII) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup (particularly pyrrolidinyl, dihydropyranyl (preferably3,6-dihydropyranyl), azetidinyl, oxetanyl or tetrahydropyranyl)optionally having 1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

(c) an oxo group, or

(XIV) an amino group (particularly 2,2-difluoroethylamino) optionallymonosubstituted or disubstituted with an optionally halogenated C₁₋₆alkyl.

As preferable examples of R³, R⁴ and R⁵,

1) ring A is a bicyclic aromatic heterocyclic ring of the formula (1),

R³ is a hydrogen atom,

R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group (particularly methoxy orethoxy), and

R⁵ is a hydrogen atom; or

2) ring A is a bicyclic aromatic heterocyclic ring of the formula (2),

R³ is a hydrogen atom, and

R⁵ is

(I) a hydrogen atom,

(II) a halogen atom (particularly chlorine),

(III) a cyano group,

(IV) a C₁₋₆ alkyl group (particularly methyl, ethyl or isopropyl)optionally having 1 to 5 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy),

(c) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly methoxy-ethoxy),

(d) a hydroxy group, and

(e) a C₁₋₆ alkyl-carbonyloxy group (particularly,2,2-dimethylpropanoyloxy),

(V) a C₁₋₆ alkoxy group (particularly methoxy),

(VI) a C₂₋₆ alkenyl group (particular 1-propenyl or ethenyl) optionallyhaving 1 to 3 (particularly 1) C₁₋₆ alkoxy groups (particularlymethoxy),

(VII) a C₂₋₆ alkynyl group (particularly ethynyl),

(VIII) a cyano-C₆₋₁₄ aryl group (particularly cyano-phenyl),

(IX) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl, isoxazolyl or pyridyl)) optionally having 1or 2 C₁₋₆ alkyl groups (particularly methyl or ethyl) optionally having1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a five- to six-membered monocyclic aromatic heterocyclic group(particularly pyridyl), and

(c) a three- to eight-membered monocyclic nonaromatic heterocyclic group(particularly morpholinyl),

(X) a C₁₋₆ alkyl-carbonyl group (particularly acetyl),

(XI) a hydroxy group,

(XII) a C₁₋₆ alkyl-five- to fourteen-membered aromatic heterocyclic oxygroup (particularly methylpyrazolyloxy),

(XIII) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup (particularly pyrrolidinyl, dihydropyranyl (preferably3,6-dihydropyranyl), azetidinyl, oxetanyl or tetrahydropyranyl)optionally having 1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

(c) an oxo group, or

(XIV) an amino group (particularly 2,2-difluoroethylamino) optionallymonosubstituted or disubstituted with an optionally halogenated C₁₋₆alkyl; or

3) ring A is a bicyclic aromatic heterocyclic ring of the formula (3),

R³ is a hydrogen atom,

R⁴ is

(I) a hydrogen atom,

(II) a halogen atom (particularly chlorine atom),

(III) an optionally halogenated C₁₋₆ alkoxy group (particularly methoxy,fluoromethoxy or difluoromethoxy), or

(IV) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl); and

R⁵ is a hydrogen atom; or

4) ring A is a bicyclic aromatic heterocyclic ring of the formula (4),

R³ is a hydrogen atom,

R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom.

As more preferable examples of R³, R⁴ and R⁵, in particular,

R³ is a hydrogen atom;

R⁴ is (a) an amino group optionally monosubstituted or disubstitutedwith a C₁₋₆ alkyl group (particularly methyl), or

(b) a C₁₋₆ alkoxy group (particularly methoxy); and

R⁵ is (a) a C₁₋₆ alkoxy group (particularly methoxy), or

(b) a C₁₋₆ alkyl group (particularly ethyl) optionally having 1 to 3hydroxy groups.

As more preferable examples of R³, R⁴ and R⁵,

1) ring A is a bicyclic aromatic heterocyclic ring of the formula (1),

R³ is a hydrogen atom,

R⁴ is a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom; or

2) ring A is a bicyclic aromatic heterocyclic ring of the formula (2),

R³ is a hydrogen atom, and

R⁵ is (a) a C₁₋₆ alkoxy group (particularly methoxy), or

(b) a C₁₋₆ alkyl group (particularly ethyl) optionally having 1 to 3(preferably 1) hydroxy groups; or

3) ring A is a bicyclic aromatic heterocyclic ring of the formula (3),

R³ is a hydrogen atom,

R⁴ is (a) an amino group optionally monosubstituted or disubstitutedwith a C₁₋₆ alkyl group (preferably methyl), or

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom; or

4) ring A is a bicyclic aromatic heterocyclic ring of the formula (4),

R³ is a hydrogen atom,

R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom.

More preferably, ring A is a bicyclic aromatic heterocyclic ringrepresented by the following formula (1)

X is N,

R¹ is a hydrogen atom, and

R⁴ is a C₁₋₆ alkoxy group (particularly methoxy).

Preferred specific examples of the compound (I) include the following.

Compound (A) which is a compound of the formula (I) or a salt thereof,wherein

R¹ is

(I) a C₁₋₆ alkyl group (particularly methyl or ethyl) optionally having1 to 5 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a hydroxy group,

(c) a cyano group,

(d) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 3 substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxy group, and

(e) a three- to eight-membered nonaromatic heterocyclic group(particularly azetidinyl) having 1 to 3 halogen atoms (particularlyfluorine atoms);

(II) a three- to eight-membered nonaromatic heterocyclic group(particularly azetidinyl or pyrrolidinyl) optionally having 1 to 5(particularly 1 or 2) substituents each selected from

(a) a C₁₋₆ alkoxy group (particularly methoxy)

(b) a halogen atom (particularly fluorine), and

(c) a hydroxy group;

(III) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl or oxazolyl)) optionally having 1 to 3(particularly 1) optionally halogenated C₁₋₆ alkyl groups (particularlymethyl or difluoromethyl);

(IV) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 5 (particularly 1) substituents each selected from

(a) a hydroxy group,

(b) a three- to eight-membered nonaromatic heterocyclic group(particularly tetrahydrofuranyl), and

(c) a five- or six-membered monocyclic aromatic heterocyclic groupoptionally having 1 to 3 (particularly 1) optionally halogenated C₁₋₆alkyl groups (particularly methyl or difluoromethyl);

(V) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularlycyclopropyl or difluorocyclobutyl); or

(VI) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl, ethyl or isobutyl) optionallyhaving 1 to 5 (particularly 1 to 3) substituents each selected from

(a) (i) a halogen atom (particularly fluorine atom),

(ii) a hydroxy group, and

(iii) a C₁₋₆ alkoxy group (particularly methoxy);

R² is

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(particularly 1) five- to fourteen-membered aromatic heterocyclic groups(particularly five- or six-membered monocyclic aromatic heterocyclicgroups (preferably oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl), isoxazolyl, isothiazolyl,thiazolyl, triazolyl (preferably 1,2,3-triazolyl or 1,2,4-triazolyl),pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, oxazolyl or furyl))optionally having 1 to 3 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine or chlorine),

(b) a C₁₋₆ alkyl group (particularly methyl, ethyl, isobutyl, isopropylor propyl) optionally having 1 to 7 (particularly 1 to 5) substituentseach selected from

(i) a halogen atom (particularly fluorine atom),

(ii) a hydroxy group, and

(iii) a C₁₋₆ alkoxy group (particularly methoxy),

(c) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularly,2,2-difluorocyclopropyl, cyclobutyl, cyclopropyl or difluorocyclobutyl(particularly 3,3-difluorocyclobutyl), fluorocyclobutyl (particularly1-fluorocyclobutyl), fluorocyclopropyl),

(d) a C₁₋₆ alkoxy group (particularly methoxy),

(e) a C₁₋₆ alkyl group-C₃₋₁₀ cycloalkyl group (particularlymethyl-cyclopropyl),

(f) a C₁₋₆ alkyl group-three- to eight-membered monocyclic nonaromaticheterocyclic group (particularly methyl-oxetanyl), and

(g) oxo group; or

(II) a C₇₋₁₆ aralkyl group (particularly benzyl) optionally having 1 to3 substituents each selected from

(a) a C₁₋₆ alkyl group (methyl or isopropyl) optionally having 1 to 3substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxyl group,

(b) a C₁₋₆ alkoxy-carbonyl group (particularly methoxycarbonyl),

(c) a halogen atom (fluorine or chlorine)

(d) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy) optionallyhaving 1 to 3 substituents each selected from

(i) a halogen atom (particularly fluorine atom), and

(ii) a hydroxyl group

(e) a mono- or di-C₁₋₆ alkyl-carbamoyl group (particularlymethylcarbamoyl),

(f) a cyano group,

(g) an amino group optionally monosubstituted or disubstituted(particularly monosubstituted) with a substituent selected from

(i) a C₁₋₆ alkyl group (particularly methyl), and

(ii) a C₁₋₆ alkoxy-carbonyl group (particularly tert-butoxy-carbonyl),

(h) a nitro group, and

(i) a carboxy group;

each of R⁶ and R⁷ is a hydrogen atom;

ring A is a bicyclic aromatic heterocyclic ring selected from theformulas (1), (2), (3) and (4);

Xs each independently represents N or C(R⁵);

R³ is a hydrogen atom;

R⁴ is (I) a hydrogen atom,

(II) a halogen atom (particularly chlorine atom),

(III) an optionally halogenated C₁₋₆ alkoxy group (particularly methoxy,fluoromethoxy, difluoromethoxy or ethoxy), or

(IV) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl);

R⁵ is (I) a hydrogen atom,

(II) a halogen atom (particularly chlorine),

(III) a cyano group,

(IV) a C₁₋₆ alkyl group (particularly methyl, ethyl or isopropyl)optionally having 1 to 5 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy),

(c) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly methoxy-ethoxy),

(d) a hydroxy group, and

(e) a C₁₋₆ alkyl-carbonyloxy group (particularly,2,2-dimethylpropanoyloxy),

(V) a C₁₋₆ alkoxy group (particularly methoxy),

(VI) a C₂₋₆ alkenyl group (particular 1-propenyl or ethynyl) optionallyhaving 1 to 3 (particularly 1) C₁₋₆ alkoxy groups (particularlymethoxy),

(VII) a C₂₋₆ alkynyl group (particularly ethynyl),

(VIII) a cyano-C₆₋₁₄ aryl group (particularly cyano-phenyl),

(IX) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl, isoxazolyl or pyridyl)) optionally having 1or 2 C₁₋₆ alkyl groups (particularly methyl or ethyl) optionally having1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a five- to six-membered monocyclic aromatic heterocyclic group(particularly pyridyl), and

(c) a three- to eight-membered monocyclic nonaromatic heterocyclic group(particularly morpholinyl),

(X) a C₁₋₆ alkyl-carbonyl group (particularly acetyl),

(XI) a hydroxy group,

(XII) a C₁₋₆ alkyl-five- to fourteen-membered aromatic heterocyclic oxygroup (particularly methylpyrazolyloxy),

(XIII) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup (particularly pyrrolidinyl, dihydropyranyl (preferably3,6-dihydropyranyl), azetidinyl, oxetanyl or tetrahydropyranyl)optionally having 1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

(c) an oxo group, or

(XIV) an amino group (particularly 2,2-difluoroethylamino) optionallymonosubstituted or disubstituted with an optionally halogenated C₁₋₆alkyl.

Compound (A′) which is the compound (A), wherein

1) ring A is a bicyclic aromatic heterocyclic ring of the formula (1),

R³ is a hydrogen atom,

R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group (particularly methoxy orethoxy),

R⁵ is a hydrogen atom; or

2) ring A is a bicyclic aromatic heterocyclic ring of the formula (2),

R³ is a hydrogen atom,

R⁵ is

(I) a hydrogen atom,

(II) a halogen atom (particularly chlorine),

(III) a cyano group,

(IV) a C₁₋₆ alkyl group (particularly methyl, ethyl or isopropyl)optionally having 1 to 5 (particularly 1 or 2) substituents eachselected from

(a) a halogen atom (particularly fluorine)

(b) a C₁₋₆ alkoxy group (particularly methoxy)

(c) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly methoxy-ethoxy)

(d) a hydroxy group, and

(e) a C₁₋₆ alkyl-carbonyloxy group (particularly,2,2-dimethylpropanoyloxy),

(V) a C₁₋₆ alkoxy group (particularly methoxy),

(VI) a C₂₋₆ alkenyl group (particular 1-propenyl or ethynyl) optionallyhaving 1 to 3 (particularly 1) C₁₋₆ alkoxy groups (particularlymethoxy),

(VII) a C₂₋₆ alkynyl group (particularly ethynyl),

(VIII) a cyano-C₆₋₁₄ aryl group (particularly cyano-phenyl),

(IX) a five- to fourteen-membered aromatic heterocyclic group(particularly five- or six-membered monocyclic aromatic heterocyclicgroup (preferably pyrazolyl, isoxazolyl or pyridyl)) optionally having 1or 2 C₁₋₆ alkyl groups (particularly methyl or ethyl) optionally having1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine atom),

(b) a five- to six-membered monocyclic aromatic heterocyclic group(particularly pyridyl), and

(c) a three- to eight-membered monocyclic nonaromatic heterocyclic group(particularly morpholinyl),

(X) a C₁₋₆ alkyl-carbonyl group (particularly acetyl),

(XI) a hydroxy group,

(XII) a C₁₋₆ alkyl-five- to fourteen-membered aromatic heterocyclic oxygroup (particularly methyl pyrazolyloxy),

(XIII) a three- to eight-membered monocyclic nonaromatic heterocyclicgroup (particularly pyrrolidinyl, dihydropyranyl (preferably3,6-dihydropyranyl), azetidinyl, oxetanyl or tetrahydropyranyl)optionally having 1 to 3 substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

(c) an oxo group, or

(XIV) an amino group (particularly 2,2-difluoroethylamino) optionallymonosubstituted or disubstituted with an optionally halogenated C₁₋₆alkyl; or

3) ring A is a bicyclic aromatic heterocyclic ring of the formula (3),

R¹ is a hydrogen atom,

R⁴ is

(I) a hydrogen atom,

(II) a halogen atom (particularly chlorine atom),

(III) an optionally halogenated C₁₋₆ alkoxy group (particularly methoxy,fluoromethoxy or difluoromethoxy), or

(IV) an amino group optionally monosubstituted or disubstituted with aC₁₋₆ alkyl group (particularly methyl); and

R⁵ is a hydrogen atom; or

4) ring A is a bicyclic aromatic heterocyclic ring of the formula (4),

R³ is a hydrogen atom,

R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom.

Compound (B) which is the compound (A), wherein

R¹ is

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3substituents each selected from

(a) a C₁₋₆ alkoxy group (particularly methoxy), and

(b) a hydroxy group;

(II) a three- to fourteen-membered nonaromatic heterocyclic group(particularly azetidinyl);

(III) a C₁₋₆ alkoxy group (particularly methoxy or ethoxy); or

(IV) an amino group;

R² is

(I) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) five- or six-membered monocyclic aromatic heterocyclicgroups (particularly oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl), isoxazolyl, thiazolyl,triazolyl (preferably 1,2,3-triazolyl or 1,2,4-triazolyl), pyrazinyl,pyrazolyl, pyridyl, pyrimidinyl or oxazolyl) optionally having 1 to 3(preferably 1) substituents each selected from

(a) a halogen atom (particularly fluorine),

(b) an optionally halogenated C₁₋₆ alkyl group (particularly methyl,difluoromethyl, trifluoromethyl, ethyl, difluoroethyl (particularly1,1-difluoroethyl), 2,2,2-trifluoroethyl, isopropyl, 1-fluoroisopropylor 1-fluoroethyl), and

(c) an optionally halogenated C₃₋₁₀ cycloalkyl group (particularly,2,2-difluorocyclopropyl, cyclobutyl, cyclopropyl or difluorocyclobutyl(particularly 3,3-difluorocyclobutyl), fluorocyclobutyl (particularly1-fluorocyclobutyl), fluorocyclopropyl); or

(II) a C₇₋₁₆ aralkyl group (particularly benzyl) optionally having 1 to3 (preferably 1 or 2) substituents each selected from

(a) a halogen atom (particularly fluorine or chlorine)

(b) an optionally halogenated C₁₋₆ alkyl group (particularlytrifluoromethyl), and

(c) an optionally halogenated C₁₋₆ alkoxy group (particularlydifluoromethoxy or trifluoromethoxy);

R³ is a hydrogen atom;

R⁴ is (a) an amino group optionally monosubstituted or disubstitutedwith a C₁₋₆ alkyl group (particularly methyl), or

(b) a C₁₋₆ alkoxy group (particularly methoxy); and

R⁵ is (a) a C₁₋₆ alkoxy group (particularly methoxy), or

(b) a C₁₋₆ alkyl group (particularly ethyl) optionally having 1 to 3hydroxy groups.

Compound (B′) which is the compound (B), wherein

1) ring A is a bicyclic aromatic heterocyclic ring of the formula (1),

R³ is a hydrogen atom,

R⁴ is a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom; or

2) ring A is a bicyclic aromatic heterocyclic ring of the formula (2),

R³ is a hydrogen atom, and

R⁵ is (a) a C₁₋₆ alkoxy group (particularly methoxy), or

(b) a C₁₋₆ alkyl group (particularly ethyl) optionally having 1 to 3(preferably 1) hydroxy groups; or

3) ring A is a bicyclic aromatic heterocyclic ring of the formula (3),

R³ is a hydrogen atom,

R⁴ is (a) an amino group optionally monosubstituted or disubstitutedwith a C₁₋₆ alkyl group (preferably methyl), or

(b) a C₁₋₆ alkoxy group (particularly methoxy), and

R⁵ is a hydrogen atom; or

4) ring A is a bicyclic aromatic heterocyclic ring of the formula (4),R³ is a hydrogen atom, R⁴ is a hydrogen atom or a C₁₋₆ alkoxy group(particularly methoxy), and R⁵ is a hydrogen atom.

Compound (C) which is the compound (B), wherein

R¹ is a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) hydroxy groups;

R² is

(1) a C₁₋₆ alkyl group (particularly methyl) optionally having 1 to 3(preferably 1) five- or six-membered monocyclic aromatic heterocyclicgroups (particularly oxadiazolyl (preferably 1,2,4-oxadiazolyl or1,3,4-oxadiazolyl), thiadiazolyl (preferably 1,2,4-thiadiazolyl),isoxazolyl) optionally having 1 to 3 (preferably 1) optionallyhalogenated C₁₋₆ alkyl groups (particularly methyl, difluoromethyl,difluoroethyl, fluoroisopropyl or fluoroethyl); or

(II) an optionally halogenated C₇₋₁₆ aralkyl group (particularlydifluorobenzyl (preferably 3,5-difluorobenzyl));

ring A is a bicyclic aromatic heterocyclic ring represented by thefollowing formula (1)

X is N;

R¹ is a hydrogen atom;

R⁴ is a C₁₋₆ alkoxy group (particularly methoxy).

In the compound (C), it is more preferable that R² is a C₁₋₆ alkyl group(particularly methyl) having 1 to 3 (preferably 1) five- or six-memberedmonocyclic aromatic heterocyclic groups (particularly oxadiazolyl(preferably 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), thiadiazolyl(preferably 1,2,4-thiadiazolyl), isoxazolyl) having 1 to 3(preferably 1) halogenated C₁₋₆ alkyl groups (particularly methyl,difluoromethyl, difluoroethyl, fluoroisopropyl or fluoroethyl).

The salt of the compound (I) is preferably a pharmacologicallyacceptable salt. Examples thereof include a salt with an inorganic base,a salt with an organic base, a salt with an inorganic acid, a salt withan organic acid and a salt with a basic or acidic amino acid.

Preferable examples of the salt with an inorganic base include: analkali metal salt such as sodium salt, potassium salt and the like; analkaline earth metal salt such as calcium salt, magnesium salt and thelike; and an aluminum salt and an ammonium salt.

Preferable examples of the salt with an organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine,benzylamine, dicyclohexylamine or N,N-dibenzylethylenediamine.

Preferable examples of the salt with an inorganic acid include a saltwith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid.

Preferable examples of the salt with an organic acid include a salt withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid.

Preferable examples of the salt with a basic amino acid include a saltwith arginine, lysine or ornithine.

Preferable examples of the salt with an acidic amino acid include a saltwith aspartic acid or glutamic acid.

The method for producing the compound of the present invention will bedescribed below.

A starting material or a reagent used in each step in the productionmethod given below and the obtained compound may each form a salt.Examples of such a salt include the same as the aforementioned salt ofthe compound of the present invention, and the like.

When the compound obtained in each step is a free compound, thiscompound can be converted to a salt of interest by a method known per sein the art. On the contrary, when the compound obtained in each step isa salt, this salt can be converted to a free form or another type ofsalt of interest by a method known per se in the art.

The compound obtained in each step may be used in the next reaction inthe form of its reaction solution or after being obtained as a crudeproduct. Alternatively, the compound obtained in each step can beisolated and/or purified from the reaction mixture by a separationapproach such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography or thelike according to a routine method.

If a starting material or a reagent compound for each step iscommercially available, the commercially available product can be useddirectly.

In the reaction of each step, the reaction time may differ depending onthe reagent or the solvent used and is usually 1 minute to 48 hours,preferably 10 minutes to 8 hours, unless otherwise specified.

In the reaction of each step, the reaction temperature may differdepending on the reagent or the solvent used and is usually −78° C. to300° C., preferably −78° C. to 150° C., unless otherwise specified.

In the reaction of each step, the pressure may differ depending on thereagent or the solvent used and is usually 1 atm to 20 atm, preferably 1atm to 3 atm, unless otherwise specified.

In the reaction of each step, a microwave synthesis apparatus, forexample, Initiator manufactured by Biotage Japan Ltd., may be used. Thereaction temperature may differ depending on the reagent or the solventused and is usually room temperature to 300° C., preferably 50° C. to250° C., unless otherwise specified. The reaction time may differdepending on the reagent or the solvent used and is usually 1 minute to48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

In the reaction of each step, the reagent is used at 0.5 equivalents to20 equivalents, preferably 0.8 equivalents to 5 equivalents, withrespect to the substrate, unless otherwise specified. In the case ofusing the reagent as a catalyst, the reagent is used at 0.001equivalents to 1 equivalent, preferably 0.01 equivalents to 0.2equivalents, with respect to the substrate. When the reagent also servesas a reaction solvent, the reagent is used in the amount of the solvent.

In the reaction of each step, this reaction is carried out without asolvent or by dissolution or suspension in an appropriate solvent,unless otherwise specified. Specific examples of the solvent include asolvent described in Examples and the following:

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;saturated hydrocarbons: cyclohexane, hexane and the like;amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;nitriles: acetonitrile and the like;sulfoxides: dimethyl sulfoxide and the like;aromatic organic bases: pyridine and the like;acid anhydrides: acetic anhydride and the like;organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;inorganic acids: hydrochloric acid, sulfuric acid and the like;esters: ethyl acetate and the like;ketones: acetone, methyl ethyl ketone and the like; and water.

Two or more of these solvents may be used as a mixture at an appropriateratio.

In the case of using a base in the reaction of each step, for example,the following base or a base described in Examples is used:

inorganic bases: sodium hydroxide, magnesium hydroxide, sodiumcarbonate, calcium carbonate, sodium hydrogen carbonate and the like;organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;alkali metal hydrides: sodium hydride and the like;metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like; andorganic lithiums: n-butyllithium and the like.

In the case of using an acid or an acidic catalyst in the reaction ofeach step, for example, the following acid or acidic catalyst or an acidor an acidic catalyst described in Examples is used:

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; andLewis acids: boron trifluoride-diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

The reaction of each step is carried out according to a method known perse in the art, for example, a method described in The Fifth Series ofExperimental Chemistry, Vol. 13 to Vol. 19 (edited by The ChemicalSociety of Japan); Shin Jikken Kagaku Koza (New Experimental Chemistryin English), Vol. 14 to Vol. 15 (edited by The Chemical Society ofJapan); Syntheses in the Organic Chemistry Laboratory, Revised, 2nd Ed.(L. F. Tietze, Th. Eicher, Nankodo Co., Ltd.); Organic Name Reactions;The Reaction Mechanism and Essence, Revised (Hideo Tougo, KodanshaLtd.); Organic Syntheses Collective Volume I to VII (John Wiley & Sons,Inc.); Modern Organic Synthesis in the Laboratory: A Collection ofStandard Experimental Procedures (Jie Jack Li, Oxford University Press);Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (ElsevierJapan KK); Strategic Applications of Named Reactions in OrganicSynthesis (translated by Kiyoshi Tomioka, published by Kagaku-DojinPublishing Company, Inc.); Comprehensive Organic Transformations (VCHPublishers, Inc.) (1989), etc., or a method described in Examples,unless otherwise specified.

In each step, the protection or deprotection reaction of a functionalgroup is carried out according to a method known per se in the art, forexample, a method described in “Protective Groups in Organic Synthesis,4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), Wiley-Interscience(2007); “Protecting Groups, 3rd Ed.” (P. J. Kocienski) Thieme MedicalPublishers (2004), etc., or a method described in Examples.

Examples of a protective group for a hydroxy group in an alcohol or aphenolic hydroxy group or the like include: an ether-type protectivegroup such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilylether, tetrahydropyranyl ether and the like; a carboxylic acidester-type protective group such as acetic acid ester and the like; asulfonic acid ester-type protective group such as methanesulfonic acidester and the like; a carbonic acid ester-type protective group such astert-butyl carbonate and the like; and the like.

Examples of a protective group for a carbonyl group in an aldehydeinclude: an acetal-type protective group such as dimethylacetal and thelike; a cyclic acetal-type protective group such as 1,3-dioxane and thelike; and the like.

Examples of a protective group for a carbonyl group in a ketone include:a ketal-type protective group such as dimethylketal and the like; acyclic ketal-type protective group such as 1,3-dioxane and the like; anoxime-type protective group such as O-methyloxime and the like; ahydrazone-type protective group such as N,N-dimethylhydrazone and thelike; and the like.

Examples of a protective group for a carboxyl group include: anester-type protective group such as methyl ester and the like; anamide-type protective group such as N,N-dimethylamide and the like; andthe like

Examples of a protective group for a thiol include: an ether-typeprotective group such as benzyl thioether and the like; an ester-typeprotective group such as thioacetic acid ester, thiocarbonate,thiocarbamate and the like; and the like.

Examples of a protective group for an amino group or an aromaticheterocycle such as imidazole, pyrrole, indole or the like include: acarbamate-type protective group such as benzyl carbamate and the like;an amide-type protective group such as acetamide and the like; analkylamine-type protective group such as N-triphenylmethylamine and thelike; a sulfonamide-type protective group such as methanesulfonamide andthe like; and the like.

These protective groups can be removed by use of a method known per sein the art, for example, a method using an acid, a base, ultravioletlight, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide) or a reductionmethod.

In the case of carrying out reduction reaction in each step, examples ofthe reducing agent used include: metal hydrides such as lithium aluminumhydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutyl aluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asa borane-tetrahydrofuran complex and the like; Raney nickel; Raneycobalt; hydrogen; formic acid; triethylsilane and the like. In the caseof reducing a carbon-carbon double bond or triple bond, a method using acatalyst such as palladium-carbon, a Lindlar's catalyst or the like canbe used.

In the case of carrying out oxidation reaction in each step, examples ofthe oxidizing agent used include: peracids such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodates such as sodium periodate and the like;a high-valent iodine reagent such as iodosylbenzene and the like; areagent having manganese, such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;a reagent having chromium, such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagents and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;a sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); and the like.

In the case of carrying out radical cyclization reaction in each step,examples of the radical initiator used include: an azo compound such asazobisisobutyronitrile (AIBN) and the like; a water-soluble radicalinitiator such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and the like;triethylboron in the presence of air or oxygen; benzoyl peroxide; andthe like. Examples of the radical reaction agent used includetributylstannane, tris(trimethylsilyl)silane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

In the case of carrying out Wittig reaction in each step, examples ofthe Wittig reagent used include alkylidenephosphoranes and the like. Thealkylidenephosphoranes can be prepared by a method known per se in theart, for example, the reaction between a phosphonium salt and a strongbase.

In the case of carrying out Horner-Emmons reaction in each step,examples of the reagent used include: phosphonoacetic acid esters suchas methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate andthe like; and a base such as alkali metal hydrides, organic lithiums andthe like.

In the case of carrying out Friedel-Crafts reaction in each step,examples of the reagent used include a combination of a Lewis acid andan acid chloride and a combination of a Lewis acid and an alkylatingagent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, anorganic acid or an inorganic acid may be used instead of the Lewis acid,and an acid anhydride such as acetic anhydride or the like may be usedinstead of the acid chloride.

In the case of carrying out aromatic nucleophilic substitution reactionin each step, a nucleophile (e.g., amines, imidazole, etc.) and a base(e.g., organic bases, etc.) are used as reagents.

In the case of carrying out nucleophilic addition reaction using acarbanion, nucleophilic 1,4-addition reaction (Michael additionreaction) using a carbanion or nucleophilic substitution reaction usinga carbanion in each step, examples of the base used for generating thecarbanion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

In the case of carrying out Grignard reaction in each step, examples ofthe Grignard reagent include: aryl magnesium halides such as phenylmagnesium bromide and the like; and alkyl magnesium halides such asmethyl magnesium bromide and the like. The Grignard reagent can beprepared by a method known per se in the art, for example, the reactionbetween alkyl halide or aryl halide and metal magnesium with ether ortetrahydrofuran as a solvent.

In the case of carrying out Knoevenagel condensation reaction in eachstep, an active methylene compound sandwiched by two electron-attractinggroups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asreagents.

In the case of carrying out Vilsmeier-Haack reaction in each step,phosphoryl chloride and an amide derivative (e.g.,N,N-dimethylformamide, etc.) are used as reagents.

In the case of carrying out azidation reaction of alcohols, alkylhalides or sulfonic acid esters in each step, examples of the azidatingagent used include diphenylphosphorylazide (DPPA), trimethylsilylazide,sodium azide and the like. In the case of azidating, for example,alcohols, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, or the like can be used.

In the case of carrying out reductive amination reaction in each step,examples of the reducing agent used include sodiumtriacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acidand the like. When the substrate is an amine compound, examples of thecarbonyl compound used include paraformaldehyde as well as aldehydessuch as acetaldehyde and the like, and ketones such as cyclohexanone andthe like. When the substrate is a carbonyl compound, examples of theamines used include: ammonia; primary amine such as methylamine and thelike; secondary amine such as dimethylamine and the like; and the like.

In the case of carrying out Mitsunobu reaction in each step,azodicarboxylic acid esters (e.g., diethyl azodicarboxylate (DEAD),diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine areused as reagents.

In the case of carrying out esterification reaction, amidation reactionor ureation reaction in each step, examples of the reagent used include:an acyl halide form such as acid chloride, acid bromide and the like;and activated carboxylic acids such as an acid anhydride, an activeester form, a sulfuric acid ester form and the like. Examples of theactivating reagent for carboxylic acid include: a carbodiimidecondensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSCD) and the like; a triazine condensing agent such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; a carbonic acid estercondensing agent such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphorylazide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide(Mukaiyama reagent); thionyl chloride; lower alkyl haloformate such asethyl chloroformate and the like;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof; andthe like. In the case of using a carbodiimide condensing agent, anadditive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide(HOSu), dimethylaminopyridine (DMAP) or the like may be further addedfor the reaction.

In the case of carrying out coupling reaction in each step, examples ofthe metal catalyst used include: a palladium compound such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; a nickel compound such astetrakis(triphenylphosphine)nickel(0) and the like; a rhodium compoundsuch as tris(triphenylphosphine)rhodium(III) chloride and the like; acobalt compound; a copper compound such as copper oxide, copper(I)iodide and the like; a platinum compound; and the like. A base may befurther added for the reaction. Examples of such a base includeinorganic base and the like.

In the case of carrying out thiocarbonylation reaction in each step,diphosphorus pentasulfide is typically used as a thiocarbonylatingagent. A reagent having a 1,3,2,4-dithiadiphosphetane-2,4-di sulfidestructure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent) or the like may be used instead of diphosphoruspentasulfide.

In the case of carrying out Wohl-Ziegler reaction in each step, examplesof the halogenating agent used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. The reaction can be accelerated by the furtheraddition of a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile or the like for the reaction.

In the case of carrying out halogenation reaction of a hydroxy group ineach step, examples of the halogenating agent used include a hydrohalicacid and an acid halide of an inorganic acid, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, and 48% hydrobromic acid and the like for bromination.Also, a method for obtaining an alkyl halide form from an alcohol by theaction of triphenylphosphine and carbon tetrachloride or carbontetrabromide or the like may be used. Alternatively, a method forsynthesizing an alkyl halide form through 2-step reactions likeinvolving the conversion of an alcohol to sulfonic acid ester and thesubsequent reaction with lithium bromide, lithium chloride or sodiumiodide may be used.

In the case of carrying out Arbuzov reaction in each step, examples ofthe reagent used include: alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite,tri(isopropyl)phosphite and the like.

In the case of carrying out sulfonic acid esterification reaction ineach step, examples of the sulfonylating agent used includemethanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonicanhydride, p-toluenesulfonic anhydride and the like.

In the case of carrying out hydrolysis reaction in each step, an acid ora base is used as a reagent. In the case of carrying out acid hydrolysisreaction of tert-butyl ester, formic acid, triethylsilane or the likemay be added for reductively trapping a by-product tert-butyl cation.

In the case of carrying out dehydration reaction in each step, examplesof the dehydrating agent used include sulfuric acid, diphosphoruspentoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

In the case of carrying out alkylation reaction in each step, examplesof the alkylating agent include optionally substituted alkyl halide(e.g., iodomethane), optionally substituted alkyl having an optionallysubstituted C₁₋₆ alkylsulfonyloxy group as a leaving group, optionallysubstituted alkyl having a C₆₋₁₄ arylsulfonyloxy group optionallysubstituted by a C₁₋₆ alkyl group. Examples of the base used includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like. In order to activate the reaction, an additive such as sodiumiodide or a quarternary ammonium salt like tetrabutylammonium iodide(TBAI) may further be added in the reaction.

Examples of the reagent to be used when an acylation reaction is carriedout in each step include activated carboxylic acids such as acyl halidessuch as acid chloride and acid bromide, active esters, esters andsulfuric acid esters. Examples of the carboxylic acid activating agentinclude carbodiimide-based condensing agents such as acid anhydrides(e.g. acetic anhydride) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents suchas 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.When a carbodiimide-based condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like may be further added to thereaction.

Examples of the halogenating agent to be used when an aromatic compoundhalogenation reaction is carried out in each step includeN-bromosuccinimide (NB S), N-iodosuccinimide (NIS), N-chlorosuccinimide(NCS), 1,3-diiodo-5,5′-dimethylhydantoin (DIH), dibromoisocyanuric acid(DBI), N-bromophthalimide, N-iodophthalimide, N-chlorophthalimide,N-bromosaccharin, N-iodosaccharin, trimethylphenylammonium tribromide,bromine, iodine and chlorine. Further, by adding a radical initiatorsuch as heat, light, benzoyl peroxide or azobisisobutyronitrile to thereaction, the reaction can be accelerated.

As a reducing agent to be used when a nitro group reduction reaction iscarried out in each step, a metal powder of reduced iron, zinc, tin orthe like is used in the Bechamp reduction method, and a catalyst such aspalladium-carbon or platinum-carbon nickel is used in the catalyticreduction method.

A ligand may be added in a reaction system when a coupling reaction iscarried out in each step, and examples of the ligand include phosphineligands [e.g. triphenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl,2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino) ferrocene, tri-tert-butylphosphine,tricyclohexylphosphine,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], amine ligands(N,N′-dimethylethylenediamine, trans-1,2-diaminocyclohexane,trans-N,N′-dimethyl-1,2-cyclohexanediamine, 1,10-phenanthroline,4,7-dimethoxy-1,10-phenanthroline,3,4,7,8-tetramethyl-1,10-phenanthroline and the like), diketone ligands(2-acetylcyclohexanone, 2-isobutyrylhexanone,2,2,6,6-tetramethyl-3,5-heptanedione and the like), salicylaldoxime, andproline.

Examples of the reagent to be used when an imidazole ring formationreaction is carried out in each step include activated carboxylic acidssuch as orthocarboxylic acid esters (e.g. trimethyl orthoacetate),N,N-dimethylcarboxylic acid amide dialkyl acetals (e.g.N,N-dimethylacetamide dimethyl acetal), imidate esters (e.g. methylacetoimidate), acyl halides such as acid chloride and acid bromide,active esters, esters and sulfuric acid esters. Examples of theactivating agent when a carboxylic acid is used includecarbodiimide-based condensing agents such as propylphosphonic anhydride(cyclic trimer), acid anhydrides (e.g. acetic anhydride) and1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (WSCD);triazine-based condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.Additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide(HOSu), dimethylaminopyridine (DMAP), an acid and a base may be furtheradded to the reaction. Alternatively, when an activated carboxylic acidor a carboxylic acid is used, a method may be used in which an imidazoleis synthesized through a two-step reaction such that a reaction with anacid or base is carried out after isolation with a carboxylic acidamide.

Examples of the reagent to be used when an alkyne synthesis reaction iscarried out in each step include α-diazophosphonate compounds(Seyferth-Gilbert Reagent and Ohira-Bestmann Reagent (e.g. dimethyl(1-diazo-2-oxopropyl)phosphonate acid)), and examples of the base to beused include organic lithiums, metal alkoxides, inorganic bases andorganic bases.

Examples of the halogenating agent to be used when a carbonyl grouphalogenation reaction is carried out in each step include thionylchloride, phosphorus oxychloride and phosphorus oxybromide.N,N-dimethylformamide may be added to the reaction for the purpose ofactivating the reaction.

When an aromatic nucleophilic substitution reaction is carried out ineach step, alcohols, thiols and salts thereof can be used asnucleophilic agents.

Hereinafter, a method for producing the compound (I), including thereaction formulas, will be described in more detail.

Each symbol in the following reaction schemes has the same meaning asdescribed above unless otherwise specified.

In addition, unless otherwise specified, raw material compounds to beused in the following various production methods can be produced by amethod known per se.

The compound (I) has the same meaning as that of the compoundrepresented by the following formula (Id) or a salt thereof.

[wherein X¹, X², X³, X⁴ and X⁵ represent one of the followingcombinations:

(X¹, X², X³, X⁴, X⁵)=(CH, N, C, CR⁴, N) (a compound represented by thiscombination is sometimes referred to as compound A1),

(CH, N, C, N, CR⁵) (a compound represented by this combination issometimes referred to as compound A2),

(CH, N, C, CR⁴, CR⁵) (a compound represented by this combination issometimes referred to as compound A3),

(N, N, C, CR⁴, CR⁵) (a compound represented by this combination issometimes referred to as compound A4),

(CH, C, N, CR⁴, N) (a compound represented by this combination issometimes referred to as compound A5),

(N, C, N, CR⁴, N) (a compound represented by this combination issometimes referred to as compound A6), and

(CH, C, N, CR⁴, CR⁵) (a compound represented by this combination issometimes referred to as compound A7); and

each symbol has the same meaning as described above.]

Hereinafter, a method for producing a compound represented by theformula (Id) or a salt thereof will be described.

[Production Method A-1i]

A compound represented by each of the formulae A5 to A7 (compoundrepresented by Ia in the following formula) or a salt thereof, and acompound represented by each of formulae A1 to A4 (compound representedby Ib in the following formula) can be produced from the compound (IIa)by the following method.

[wherein V¹ and V² are the same or different, and each represent aleaving group (e.g. hydrogen, an alkali metal (e.g. lithium or sodiumsodium), a halogen atom (e.g. fluorine, chlorine, bromine or iodine), aC₁₋₆ alkoxy group (e.g. methoxy), a C₆₋₁₄ aryloxy group (e.g. phenoxy),an optionally substituted acyl-oxy group (e.g. acetyloxy or benzoyloxy),an optionally substituted C₁₋₆ alkoxysulfonyloxy group (e.g.methoxysulfonyloxy), an optionally halogenated C₁₋₆ alkylsulfonyl-oxygroup (e.g. methanesulfonyloxy, ethanesulfonyloxy,trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate)), oran optionally substituted C₆₋₁₄ arylsulfonyl-oxy group (e.g. a C₆₋₁₄arylsulfonyloxy group (e.g. benzenesulfonyloxy,m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy or naphthylsulfonyloxy)optionally having 1 to 3 substituents each selected from a C₁₋₆ alkylgroup (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl), a C₁₋₆ alkoxy group (e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,pentyloxy or hexyloxy) and a nitro group; U represents a boryl group(e.g.

etc.), an optionally substituted C₁₋₆ alkylstannyl group (e.g.tributylstannyl or the like), an optionally substituted C₂₋₆alkenylstannyl group, or an optionally substituted C₁₋₆ alkynylstannylgroup; and

each of other symbols has the same meaning as described above.]

The compound (IV) in which U is a boryl group can be produced by aborylation reaction of the compound (IIa). The borylation reactionincludes a method using a Miyaura-Ishiyama-Hartwig borylation reactionand a transmetalation reaction as described below, and by using eachreaction, a compound (IV) in which U is a boryl group can be produced.

i) Method Using Miyaura-Ishiyama-Hartwig Borylation Reaction

The compound (IV) in which U is a boryl group can be produced byreacting the compound (IIa) and a borylating agent under a metalcatalyst and a base (specifically Miyaura-Ishiyama-Hartwig borylationreaction). Preferably, this reaction is carried out under an inert gasatmosphere. This reaction may be carried out in the presence of a ligandand even under microwave irradiation.

Specific examples of the borylating agent include bis(pinacolato)diboronand pinacol borane. Specific examples of the metal catalyst includepalladium compounds such as palladium (II) acetate,tetrakis(triphenylphosphine)palladium (0),dichlorobis(triphenylphosphine)palladium (II),dichlorobis(triethylphosphine)palladium (II),tris(dibenzylideneacetone)dipalladium (0),1,1′-bis(diphenylphosphino)ferrocenepalladium (II) chloride andpalladium (II) acetate; nickel compounds such astetrakis(triphenylphosphine)nickel (0); rhodium compounds such astris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; coppercompounds such as copper oxide and copper (I) iodide; platinumcompounds; and iridium compounds. Specific examples of the ligandinclude phosphine ligands [e.g. triphenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl,2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl,1,1′-bis(diphenylphosphino) ferrocene, tri-tert-butylphosphine,tricyclohexylphosphine,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], amine ligands(N,N′-dimethylethylenediamine, trans-1,2-diaminocyclohexane,trans-N,N′-dimethyl-1,2-cyclohexanediamine, 1,10-phenanthroline,4,7-dimethoxy-1,10-phenanthroline,3,4,7,8-tetramethyl-1,10-phenanthroline and the like), diketone ligands(2-acetylcyclohexanone, 2-isobutyrylhexanone,2,2,6,6-tetramethyl-3,5-heptanedione and the like), salicylaldoxime, andproline.

ii) Method Using Transmetalation Reaction

The compound (IV) in which U is a boryl group can be produced byreacting the compound (IIa) with a borylating agent in the presence ofan organometallic reagent (e.g. organolithium, metal alkoxide, alkalimetal hydride, metal amide or isopropyl magnesium chloride)(specifically transmetalation reaction). Specific examples of theborylating agent include trialkoxyboranes (e.g. trimethoxyborane,triethoxyborane and triisopropoxyborane).

The compound (IV) in which U is an optionally substituted C₁₋₆alkylstannyl group (e.g. tributylstannyl or the like), an optionallysubstituted C₂₋₆ alkenylstannyl group, or an optionally substituted C₁₋₆alkynylstannyl group can be produced by a stannylation reaction of thecompound (IIa). This reaction is carried out by reacting the compound(IIa) with a stannylating agent in the presence of an organometallicreagent (e.g. organolithium, metal alkoxide, alkali metal hydride ormetal amide). Specific examples of the stannylating agent includetrimethyl tin chloride, triphenyl tin chloride, trimethyl tin acetate,dimethyl tin dichloride, dibutyl tin dichloride, dimethyl tin diacetateand dibutyl tin diacetate.

[Production Method A-2]

The compound (Id) can also be produced from a compound (Ic) contained inthe compound (Id) by the following method.

[wherein V³ represents a halogen atom (e.g. fluorine, chlorine, bromineor iodine); and

each of other symbols has the same meaning as described above.]

[Production Method A-3]

The compound (Id) can also be produced from a compound (Ie) contained inthe compound (Id) by the following method.

[Production Method A-4]

The compound represented by the formula A1 or each of the formulae A3 toA7 (compound represented by Ii in the following formula) or a saltthereof can be produced from a compound (Ig) contained in the compound(Ii) by the following method.

[wherein V⁴ represents a halogen atom (e.g. flourine, chlorine, bromineor iodine); and

each of other symbols has the same meaning as described above.]

A compound (Ih) can be produced by a halogenation reaction of a methoxygroup of the compound (Ig). This reaction can be carried out similarlyto the halogenation reaction of a carbonyl group.

[Production Method A-5]

The compound represented by each of the formulae A2 to A4 or formula A7(compound represented by Id′ in the following formula) or a salt thereofcan be produced from a compound each of other symbols has the samemeaning as described above.](Ij) contained in the compound (Id′) by thefollowing method.

[wherein V⁵ represents a halogen atom (e.g. fluorine, chlorine, bromineor iodine); and

each of other symbols has the same meaning as described above.]

[Production Method A-6]

A compound (II) contained in the compound (Id′) can be produced from acompound (Ik) contained in the compound (Id′) by the following method.

[wherein each symbol has the same meaning as described above.]

[Production Method A-7]

Compounds (Io), (Iq) and (Ir) contained in the compound (Id′) can beproduced from a compound (Im) contained in the compound (Id′) by thefollowing method.

[wherein P¹ represents a protecting group for a hydroxyl group;

R^(5a) represents a hydrogen atom, a group bonded via a carbon atom, agroup bonded via a nitrogen atom or a group bonded via an oxygen atom;

R^(5b) represents a group bonded via a carbon atom; and each of othersymbols has the same meaning as described above.]

Compound (Ir) can be produced by a fluorination reaction of a compound(Ip). This reaction can be carried out in accordance with a method knownper se [e.g. Journal of Medicinal Chemistry, 33(1), 142-6 (1990),Journal of Medicinal Chemistry, 55(21), 9346-9361 (2012), Journal ofMedicinal Chemistry, 50(15), 3427-3430 (2007), Bioorganic & MedicinalChemistry Letters, 20 (16), 4753-4756 (2010), Journal of MedicinalChemistry, 50(20), 5024-5033 (2007), Tetrahedron, 65(33), 6611-6625(2009), Synlett, (14), 2111-2114 (2008), Organic Process Research &Development, 14(2), 393-404 (2010), and Bioorganic & MedicinalChemistry, 23(2), 297-313 (2015)], or a similar method.

[Production Method B-1]

The compound (IIa) to be used in [Production method A-1] can be producedby the following method.

[wherein R^(2a) represents an optionally substituted aromatic ring, anoptionally substituted aromatic heterocyclic ring, or an optionallysubstituted nonaromatic heterocyclic ring; and

each of other symbols has the same meaning as described above.]

The compound (IIa) can be produced by a dehydration cyclization reactionof a compound (IX). This reaction can also be carried out by heating.Further, this reaction can also be carried out by heating in thepresence of an acid (e.g. inorganic acid, organic acid, Lewis acid orthe like) or a base (e.g. organolithium, metal alkoxide, inorganic base,organic base or the like).

A compound (V) is available as a commercially available product, or isproduced by a method known per se.

[Production Method B-2]

The compound (IIa) to be used in [Production method A-1] can be producedfrom a compound (VI) by the following method.

[wherein V⁶ represents a halogen atom (e.g. fluorine, chlorine, bromineor iodine); and

each of other symbols has the same meaning as described above.]

A compound (X) can be produced by a cyclization reaction of the compound(VI) using a carbonylating reagent. Examples of the carbonylatingreagent include 1,1′-carbonylbis-1H-imidazole, diphosgene, triphosgeneand phenyl chloroformate. The reaction can also be carried out in thepresence of a base. Examples of the base include organic bases,inorganic bases and basic salts.

The compound (XI) can be produced by a cyclization reaction of thecompound (VI) using a thiocarbonylating reagent. Examples of thethiocarbonylating reagent include carbon disulfide, thiourea, ethylxanthate, thiophosgene and 1,1′-thiocarbonyldiimidazole. This reactioncan also be carried out in the presence of a base. Examples of the baseinclude organic bases, inorganic bases and basic salts.

A compound (IIc) can be produced by a halogenation reaction of athiocarbonyl group of the compound (XI). This reaction can be carriedout similarly to the halogenation reaction of a carbonyl group.

[Production Method B-3]

A compound (IIe), a compound (IIh), a compound (IIk) and a compound(IIl) contained in the compound (IIa) to be used in [Production MethodA-1] can be produced by the following method.

[wherein R^(2b) and R^(2d) each independently represent a hydrogen atom,a group bonded via a halogen atom or a carbon atom, a group bonded via anitrogen atom, a group bonded via an oxygen atom, or a group bonded viaa sulfur atom;

R^(2c) represents a group bonded via a carbon atom; and each of othersymbols has the same meaning as described above.]

A compound (IId) can be produced by an amidination reaction of a cyanogroup of a compound (IIf). This reaction can be carried out inaccordance with a method known per se [e.g. Bioorganic & MedicinalChemistry Letters, 20(19), 5735-5738 (2010), Tetrahedron, 45(20),6511-18 (1989), Journal of Organic Chemistry, 53(5), 1085-7 (1988),European Journal of Medicinal Chemistry, 16(2), 175-9 (1981), Journal ofMedicinal Chemistry, 33(4), 1230-41 (1990), European Journal ofMedicinal Chemistry, 60, 395-409(2013), Journal of Organic Chemistry,69(20), 6572-6589 (2004), Journal of Labelled Compounds andRadiopharmaceuticals, 56(14), 722-725 (2013), European Journal ofMedicinal Chemistry, 103, 29-43 (2015), European Journal of OrganicChemistry, 2014(17), 3614-3621 (2014), and Journal of the AmericanChemical Society, 107(9), 2743-8 (1985)], or a similar method.

A compound (IIi) can be produced by subjecting a cyano group of thecompound (IIf) to a hydroxyamidation reaction in the presence of ahydroxyamidinating reagent. Examples of the hydroxyamidinating reagentinclude hydroxyamine or a salt thereof. This reaction can be carried outin the presence of an acid or a base. Examples of the acid includeinorganic acids, organic acids and Lewis acids. Examples of the baseinclude organic lithiums, metal alkoxides, inorganic bases and organicbases.

A compound (IIg) can be produced by subjecting a cyano group of thecompound (IIf) to a thioamidation reaction in the presence of athioamidating reagent. Examples of the thioamidating reagent includephosphorus pentasulfide, hydrogen sulfide,2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lowesson reagent), dialkyl dithiophosphates (e.g. O,O′-diethyldithiophosphate).

The compound (IIe) can be produced by subjecting the compound (IId) to apinner pyrimidine synthesis reaction in the presence of a reagent.Examples of the reagent include a 1,3-dicarbonyl compounds andα,β-unsaturated carbonyl compounds. This reaction can be carried out inthe presence of a base. Examples of the base include organic lithiums,metal alkoxides, inorganic bases and organic bases.

The compound (IIh) can be produced by subjecting the compound (IIg) to a1,2,4-thiadiazole ring formation reaction in the presence of a reagent.Examples of the reagent include N,N-dialkylcarboxylic acid amide dialkylacetals (e.g. N,N-dimethylacetamide dimethyl acetal) and hydroxyaminederivatives (e.g. hydroxylamine-O-sulfonic acid). This reaction can becarried out through a two-step reaction such that by the aN,N-dialkylcarboxylic acid amide dialkyl acetal is reacted with thecompound (IIg) to isolate a N-(dialkylaminomethylene)thiocarbonyl, andthe isolated N-(dialkylaminomethylene)thiocarbonyl is reacted with ahydroxyamine derivative.

The compound (Ill) can be produced by subjecting the compound (IIi) to a1,2,4-oxadiazole ring formation reaction in the presence of a reagent.Examples of the reagent include activated carboxylic acids such as acylhalides such as acid chloride and acid bromide, active esters, estersand sulfuric acid esters. Examples of the activating agent inpreparation of the activated carboxylic acid include carbodiimide-basedcondensing agents such as propylphosphonic anhydride (cyclic trimer),acid anhydrides (e.g. acetic anhydride) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD);triazine-based condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethyl aminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.When the reaction is carried out, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), an acid and a base can be added to theactivating agent.

[Production Method B-4]

A compound (IIo) and a compound (IIq) contained in the compound (IIa) tobe used in [Production Method A-1] can be produced from a compound (IIm)contained in the compound (IIa) by the following method.

[wherein P² represents a protecting group for a carboxyl group, and

each of other symbols has the same meaning as described above.]

The compound (IIo) can be produced by subjecting a carboxyl group of thecompound (IIn) to a 1,2,4-oxadiazole cyclization reaction in thepresence of a reagent. Examples of the reagent include hydroxyamidines(e.g. N-hydroxyacetamidine). Examples of the carboxylic acid activatingagent to be used in the reaction include carbodiimide-based condensingagents such as propylphosphonic anhydride (cyclic trimer), acidanhydrides (e.g. acetic anhydride) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents suchas 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethyl aminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.When the reaction is carried out, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), an acid and a base can be added to theactivating agent.

The compound (IIq) can be produced by subjecting a carboxyl group of thecompound (IIn) to a 1,3,4-oxadiazole cyclization reaction in thepresence of a reagent. Examples of the reagent include hydrazides (e.g.acetohydrazide). Examples of the carboxylic acid activating agent to beused in the reaction include carbodiimide-based condensing agents suchas thionyl chloride, phosphorus oxychloride, phosphorus oxybromide,propylphosphonic anhydride (cyclic trimer), acid anhydrides (e.g. aceticanhydride) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (WSCD); triazine-based condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.When the reaction is carried out, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), an acid and a base can be added to theactivating agent.

This reaction can be carried out through a two-step reaction such thatN,N′-diacylhydrazine is isolated, and the isolated N,N′-diacylhydrazineis subjected to a dehydration reaction in the presence of a sulfonatingagent (e.g. methanesulfonyl chloride, p-toluenesulfonyl chloride,methanesulfonic anhydride or p-toluenesulfonic anhydride) or adehydrating agent (e.g. sulfuric acid, diphosphorus pentoxide,phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide, alumina orpolyphosphoric acid).

The compound (IIq) can be produced by subjecting a hydrazide group of acompound (IIp) to a 1,3,4-oxadiazole cyclization reaction in thepresence of a reagent. Examples of the reagent include activatedcarboxylic acids such as acyl halides such as acid chloride and acidbromide, active esters, esters and sulfuric acid esters. Examples of thecarboxylic acid activating agent when a carboxylic acid is used includecarbodiimide-based condensing agents such as thionyl chloride,phosphorus oxychloride, phosphorus oxybromide, propylphosphonicanhydride (cyclic trimer), acid anhydrides (e.g. acetic anhydride) and1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD);triazine-based condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM); carbonic acid ester-based condensing agentssuch as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salts (BOP reagents);2-chloro-1-methyl-pyridinium iodide (Mukaiyama Reagent); thionylchloride; haloformic acid lower alkyls such as ethyl chloroformate;O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof.When the reaction is carried out, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), an acid and a base can be further added tothe activating agent.

This reaction can be carried out through a two-step reaction such thatN,N′-diacylhydrazine is isolated, and the isolated N,N′-diacylhydrazineis subjected to a dehydration reaction in the presence of a sulfonatingagent (e.g. methanesulfonyl chloride, p-toluenesulfonyl chloride,methanesulfonic anhydride or p-toluenesulfonic anhydride) or adehydrating agent (e.g. sulfuric acid, diphosphorus pentoxide,phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide, alumina orpolyphosphoric acid).

A compound (IIr) can be produced by subjecting a hydrazide group of acompound (IIp) to a 1,3,4-thiadiazole cyclization reaction in thepresence of a reagent. Examples of the reagent include thiocarbonylatingreagents (e.g. diphosphorus pentasulfide,2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lowesson reagent), and activated carboxylic acids such as acyl halidessuch as acid chloride and acid bromide, active esters, esters andsulfuric acid esters. Examples of the activating agent when a carboxylicacid is used include activating agents similar to those mentioned ascarboxylic acid activating agents usable in production of the compound(IIq) from the compound (IIp).

[Production Method C-1]

A compound (IIIa) to be used in [Production Method A-1] can be producedby the following method.

[wherein each symbol has the same meaning as described above.]

The compound (IIIa) can be produced by a borylation reaction or astannylation reaction of the compound (IIIb). The method for thereaction is similar to the method described in [Production Method A-1].

A compound (IIIb) is available as a commercially available product, oris produced by a method known per se.

When a substituent of the compound (I) thus obtained is converted byapplying means known per se (i.e. introduction of a substituent orconversion of a functional group), another compound included in thecompound (I), or a salt thereof can be produced.

As a method for introduction of a substituent or conversion of afunctional group, a general known method is used, and examples thereofinclude conversion of a halogen atom (e.g. fluorine, chlorine, bromineor iodine) or an optionally halogenated C₁₋₆ alkylsulfonyl-oxy group[e.g. methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxyor trifluoromethanesulfonyloxy (triflate)] into a methyl group, acyclopropyl group, a vinyl group, a cyano group, a formyl group, acarbonyl group, a carboxyl group, a hydroxyl group, an amino group, aboryl group or the like; conversion of a formyl group into an ethynylgroup by Seyferth-Gilbert homologation; conversion of an ester into acarboxy group by hydrolysis; conversion of a carboxy group into acarbamoyl group by amidation; conversion of a carboxy group into ahydroxymethyl group by reduction; conversion of a carbonyl group into analcohol by reduction or alkylation; reductive amination of a carbonylgroup; oximation of a carbonyl group; acylation of an amino group; ureaformation of an amino group; sulfonylation of an amino group; alkylationof an amino group; substitution or amination of an active halogen by anamine; alkylation of a hydroxy group; and substitution or amination of ahydroxy group.

When a reactive part in which an unintended reaction takes place in theintroduction of a substituent or conversion of a functional group ispresent, a compound falling within the scope of the present inventioncan be produced by introducing a protecting group into the reactive partbeforehand by means known per se as necessary, carrying out an intendedreaction, and then removing the protecting group by means known per se.

For example, when a raw material compound or an intermediate has anamino group, a carboxyl group or a hydroxyl group as a substituent, thegroup may be protected with a protecting group that is generally usedpeptide chemistry etc. In this case, a target compound can be obtainedby removing the protective group as necessary after the reaction.

When a substituent of the compound (I) thus obtained is converted byapplying means known per se (i.e. introduction of a substituent orconversion of a functional group), another compound included in thecompound (I), or a salt thereof can be produced.

As a method for introduction of a substituent or conversion of afunctional group, a general known method is used, and examples thereofinclude conversion of a halogen atom (e.g. fluorine, chlorine, bromineor iodine) or an optionally halogenated C₁₋₆ alkylsulfonyl-oxy group[e.g. methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxyor trifluoromethanesulfonyloxy (triflate)] into a methyl group, acyclopropyl group, a vinyl group, a cyano group, a formyl group, acarbonyl group, a carboxyl group, a hydroxyl group, an amino group, aboryl group or the like; conversion of a formyl group into an ethynylgroup by Seyferth-Gilbert homologation; conversion of an ester into acarboxy group by hydrolysis; conversion of a carboxy group into acarbamoyl group by amidation; conversion of a carboxy group into ahydroxymethyl group by reduction; conversion of a carbonyl group into analcohol by reduction or alkylation; reductive amination of a carbonylgroup; oximation of a carbonyl group; acylation of an amino group; ureaformation of an amino group; sulfonylation of an amino group; alkylationof an amino group; substitution or amination of an active halogen by anamine; alkylation of a hydroxy group; and substitution or amination of ahydroxy group.

When a reactive part in which an unintended reaction takes place in theintroduction of a substituent or conversion of a functional group ispresent, a compound falling within the scope of the present inventioncan be produced by introducing a protecting group into the reactive partbeforehand by means known per se as necessary, carrying out an intendedreaction, and then removing the protecting group by means known per se.

For example, when a raw material compound or an intermediate has anamino group, a carboxyl group or a hydroxyl group as a substituent, thegroup may be protected with a protecting group that is generally usedpeptide chemistry etc. In this case, a target compound can be obtainedby removing the protective group as necessary after the reaction.

When the compound (I) has isomers such as optical isomers,stereoisomers, regioisomers and rotational isomers, the compound (I)encompasses any one of the isomers and mixtures of the isomers. Forexample, when the compound (I) has optical isomers, the compound (I)also encompasses optical isomers divided from racemates. Each of theseisomers can be obtained as a single product by a synthesis method orseparation method known per se (e.g. concentration, solvent extraction,column chromatography or recrystallization).

The compound (I) may be in the form of a crystal, and the compound (I)encompasses either a single crystal form or a crystal form mixture. Thecrystal can be produced by performing crystallization using acrystallization method known per se.

In addition, the compound (I) may be in the form of a pharmaceuticallyacceptable cocrystal or cocrystal salt. Here, the cocrystal or cocrystalsalt means a crystalline substance composed of two or more unique solidsat room temperature, which have different physical properties (e.g.structure, melting point, heat of fusion, hygroscopic property andstability). The cocrystals or cocrystal salt can be produced inaccordance with a cocrystallization method known per se.

The compound (I) may be any of a hydrate, a non-hydrate, a solvate and anon-solvate, all of which are encompassed in the compound (I).

The compound (I) also encompasses compounds each labeled with an isotope(e.g. ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S or ¹²⁵I) or the like. The compound (I)labeled or substituted with an isotope can be used as, for example, atracer (PET tracer) that is used in positron emission tomography (PET),and may be useful in the field of medical diagnosis etc.

The compound (I) may be a prodrug.

The prodrug of the compound (I) is a compound that is converted into thecompound (I) by a reaction with an enzyme, gastric acid or the likeunder physiological conditions in a living body, i.e. a compound that isenzymatically oxidized, reduced or hydrolyzed to change into thecompound (I), or a compound that is hydrolyzed by gastric acid etc. tochange into the compound (I).

Examples of the prodrug of the compound (I) include:

(1) compounds in which the amino of the compound (I) is acylated,alkylated or phosphorylated (e.g. compounds in which the amino of thecompound (I) is eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated, ethoxycarbonylated, tert-butoxycarbonylated, acetylatedor cyclopropylcarbonylated);

(2) compounds in which the hydroxy of the compound (I) is acylated,alkylated, phosphorylated or borated (e.g. compounds in which thehydroxy of the compound (I) is acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated); and

(3) compounds in which the carboxy of the compound (1) is esterified oramidated (e.g. carboxy of the compound (I) is ethyl-esterified,phenyl-esterified, carboxymethyl-esterified,dimethylaminomethyl-esterified, pivalolyloxymethyl-esterified,ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified,cyclohexyloxycarbonylethyl-esterified or methylamidated). Thesecompounds can be produced from the compound (I) by a method known perse.

In addition, the prodrug of the compound (I) is a compound which ischanged into the compound (I) under physiological conditions asdescribed in “Development of Pharmaceuticals” published by HirokawaShoten Co., 1990, Vol. 7, Molecular Design, pages 163 to 198.

In this specification, the prodrug may form a salt, and examples of thesalt include salts exemplified as the salt of the compound representedby the formula (I).

The compound (I) or prodrug thereof (herein sometimes abbreviated as a“present invention compound” collectively) has CLK inhibitory activity,and may be useful as a prophylactic or therapeutic agent for cancer, acancer growth inhibitor, or cancer metastasis inhibitor.

The present invention compound may be useful as a medicament because thepresent invention compound exhibits selective inhibitory activityagainst CLK, and is excellent in development of pharmacological effects,pharmacokinetics (e.g. absorbability, distribution, metabolism andexcretion), solubility (e.g. water solubility), interaction with otherpharmaceutical products (e.g. drug metabolizing enzyme inhibitoryaction), safety (in terms of, for example, acute toxicity, chronictoxicity, genotoxicity, reproductive toxicity, cardiotoxicity,carcinogenicity and central toxicity) and stability (e.g. chemicalstability and stability against enzymes).

Since the present invention compound has low inhibitory activity againstSCD family subtypes other than SCDI, the present invention compound maybe useful as a prophylactic/therapeutic agent for cancer, which hasreduced toxicity to normal cells.

Therefore, the compound of the present invention can be used forinhibiting excess (abnormal) CLK action on mammals (e.g. mouse, rat,hamster, rabbit, cat, dog, bovine, ovine, monkey and human).

The present invention compound can be used as a medicament such as aprophylactic or therapeutic agent for diseases which may be influencedby CLK (herein, sometimes abbreviated as “CLK related diseases”), forexample cancers [e.g. colorectal cancer (e.g. colon cancer, rectalcancer, anal cancer, familial colorectal cancer, hereditary nonpolyposiscolorectal cancer and gastrointestinal stromal tumor), lung cancer (e.g.non-small-cell lung cancer, small cell lung cancer and malignantmesothelioma), mesothelioma, pancreatic cancer (e.g. pancreatic ductalcarcinoma and pancreatic endocrine tumor), pharyngeal cancer, laryngealcancer, esophageal cancer, stomach cancer (e.g. papillaryadenocarcinoma, mucous adenocarcinoma and adenosquamous carcinoma),duodenal carcinoma, small intestinal cancer, breast cancer (e.g.infiltrating duct carcinoma, noninfiltrating intraductal carcinoma andinflammatory breast cancer), ovarian cancer (e.g. epithelial ovariancancer, extragonadal germ cell tumor, ovarian germ cell tumor andovarian low malignant potential tumor), testicular tumor, prostaticcancer (e.g. hormone-dependent prostatic cancer, hormone-independentprostatic cancer and castration-resistant prostatic cancer), livercancer (e.g. hepatic cell carcinoma, primary hepatic cancer and cancerof extrahepatic bile duct), thyroid cancer (e.g. thyroid medullarycarcinoma), kidney cancer (e.g. renal cell carcinoma (e.g. clear celltype renal cell carcinoma) and transitional cell carcinoma of renalpelvis and ureter), uterine cancer (e.g. cervical cancer, corpus utericancer and uterine sarcoma), gestational choriocarcinoma, brain tumor(e.g. medulloblastoma, glioma, pineal astrocytoma, pilocyticastrocytoma, diffuse astrocytoma, anaplastic astrocytoma and pituitaryadenoma), retinoblastoma, skin cancer (e.g. basal cell carcinoma andmalignant melanoma), sarcoma (e.g. rhabdomyosarcoma, leiomyosarcoma,soft tissue sarcoma and spindle cell sarcoma), malignant bone tumor,bladder cancer, blood cancer (e.g. multiple myeloma, leukemia (e.g.acute myeloid leukemia), malignant lymphoma, Hodgkin's disease andchronic myeloproliferative disease), and cancer of unknown primary], acancer growth inhibitor, a cancer metastasis inhibitor, an apoptosispromoting agent, or a therapeutic agent for precancerous lesion (e.g.osteomyelodysplasia syndrome).

In particular, the present invention compound can be used as amedicament for osteomyelodysplasia syndrome, acute myeloid leukemia,multiple myeloma or breast cancer.

From a different point of view, the present invention compound may beuseful as a prophylactic or therapeutic agent, a growth inhibitor or ametastasis inhibitor for

(i) cancer in which splicing is abnormal (e.g. osteomyelodysplasiasyndrome, acute myeloid leukemia, lymphoma, lung cancer, pancreaticcancer, breast cancer, melanoma, bladder cancer and head and neckcancer)

(ii) cancer in which Myc (specifically c-Myc, N-Myc or L-Myc) isactivated (e.g. lymphoma, multiple myeloma, neuroblastoma, breast cancerand lung cancer), and

(iii) high-CLK expressing cancer (e.g. breast cancer and multiplemyeloma).

The compound of the present invention can be orally or parenterallyadministered as a medicament containing the compound of the presentinvention alone or as a mixture with a pharmacologically acceptablecarrier to a mammal (preferably a human).

Hereinafter, the medicament comprising the compound of the presentinvention (also referred to as the “medicament of the presentinvention”) will be described in detail. Examples of the dosage form ofthe medicament of the present invention include an oral preparation suchas tablets (e.g., sugar-coated tablets, film-coated tablets, sublingualtablets, buccal tablets and rapidly orally disintegrating tablets),pills, granules, powders, capsules (e.g., soft capsules andmicrocapsules), syrups, emulsions, suspensions, films (e.g., orallydisintegrating films and patch films for application to the oral mucosa)and the like. Other examples of the dosage form of the medicament of thepresent invention include a parenteral preparation such as injections,transfusions, transdermal preparations (e.g., iontophoresis dermalpreparations), suppositories, ointments, transnasal preparations,transpulmonary preparations, eye drops and the like. Alternatively, themedicament of the present invention may be a controlled-releasepreparation such as a rapid-release preparation, a sustained-releasepreparation (e.g., a sustained-release microcapsule) or the like.

The medicament of the present invention can be produced by a productionmethod known in the art (e.g., a method described in JapanesePharmacopoeia) generally used in the field of pharmaceutical technology.If necessary, the medicament of the present invention can appropriatelycontain an appropriate amount of an additive usually used in thepharmaceutical field, such as an excipient, a binder, a disintegrant, alubricant, a sweetener, a surfactant, a suspending agent, an emulsifier,a colorant, a preservative, a fragrance, a corrigent, a stabilizer, aviscosity modifier and the like.

Examples of the pharmacologically acceptable carrier described aboveinclude these additives.

For example, the tablets can be produced using an excipient, a binder, adisintegrant, a lubricant and the like. The pills and the granules canbe produced using an excipient, a binder and a disintegrant. The powdersand the capsules can be produced using an excipient and the like. Thesyrups can be produced using a sweetener and the like. The emulsions orthe suspensions can be produced using a suspending agent, a surfactant,an emulsifier and the like.

Examples of the excipient include lactose, saccharose, glucose, starch,sucrose, microcrystalline cellulose, licorice powder, mannitol, sodiumhydrogen carbonate, calcium phosphate and calcium sulfate.

Examples of the binder include a solution containing 5 to 10% by weightof starch paste, a solution containing 10 to 20% by weight of gum arabicor gelatin, a solution containing 1 to 5% by weight of tragacanth, acarboxymethylcellulose solution, a sodium alginate solution andglycerin.

Examples of the disintegrant include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate,carboxymethylcellulose sodium, methylcellulose and bentonite.

Examples of the emulsifier include gum arabic, tragacanth, gelatin andpolysorbate 80.

When the medicament of the present invention is, for example, tablets,the tablets can be produced according to a method known per se in theart by adding, for example, an excipient (e.g., lactose, saccharose,starch), a disintegrant (e.g., starch, calcium carbonate), a binder(e.g., starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose) or a lubricant (e.g., talc, magnesium stearate,polyethylene glycol 6000) to the compound of the present invention andmolding the mixture by compression, followed by coating, if necessary,by a method known per se in the art for the purpose of taste masking,enteric properties or durability. For example,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethylcellulose acetate succinate, Eudragit (manufactured by RohmGmbH, Germany, methacrylic acid-acrylic acid copolymer) and a dye (e.g.,iron red, titanium dioxide) can be used as coating agents for thecoating.

The injections include intravenous injections as well as subcutaneousinjections, intracutaneous injections, intramuscular injections,intraperitoneal injections, drip injections and the like.

Such injections are prepared by a method known per se in the art, i.e.,by dissolving, suspending or emulsifying the compound of the presentinvention in a sterile aqueous solution or oily solution. Examples ofthe aqueous solution include saline, an isotonic solution containingglucose or an additional adjuvant (e.g., D-sorbitol, D-mannitol, sodiumchloride) and the like. The aqueous solution may contain an appropriatesolubilizing agent, for example, an alcohol (e.g., ethanol), apolyalcohol (e.g., propylene glycol, polyethylene glycol) or a nonionicsurfactant (e.g., polysorbate 80, HCO-50). Examples of the oily solutioninclude sesame oil, soybean oil and the like. The oily solution maycontain an appropriate solubilizing agent. Examples of the solubilizingagent include benzyl benzoate, benzyl alcohol and the like. Theinjections may be further supplemented with a buffer (e.g., a phosphatebuffer solution, a sodium acetate buffer solution), a soothing agent(e.g., benzalkonium chloride, procaine hydrochloride), a stabilizer(e.g., human serum albumin, polyethylene glycol), a preservative (e.g.,benzyl alcohol, phenol) or the like. Ampules can usually be filled withthe prepared injection solutions.

The content of the compound of the present invention in the medicamentof the present invention differs depending on the form of thepreparation and is usually approximately 0.01 to approximately 100% byweight, preferably approximately 2 to approximately 85% by weight, morepreferably approximately 5 to approximately 70% by weight, with respectto the whole preparation.

The content of the additive in the medicament of the present inventiondiffers depending on the form of the preparation and is usuallyapproximately 1 to approximately 99.9% by weight, preferablyapproximately 10 to approximately 90% by weight, with respect to thewhole preparation.

The compound of the present invention can be used stably, low toxicallyand safely. The daily dose of the compound of the present inventiondiffers depending on the status and body weight of a patient, the typeof the compound, an administration route, etc. In the case of, forexample, oral administration to a patient for the purpose of treatingcancer, the daily dose in adult (body weight: approximately 60 kg) canbe approximately 1 to approximately 1000 mg, preferably approximately 3to approximately 300 mg, more preferably approximately 10 toapproximately 200 mg, of the compound of the present invention, whichcan be administered in one portion or in two or three portions.

In the case of parenterally administering the compound of the presentinvention, the compound of the present invention is usually administeredin the form of a solution (e.g., an injection). The single dose of thecompound of the present invention also differs depending on a recipient,a target organ, symptoms, an administration method, etc. For example,usually approximately 0.01 to approximately 100 mg, preferablyapproximately 0.01 to approximately 50 mg, more preferably approximately0.01 to approximately 20 mg, of the compound of the present inventionper kg of body weight can be administered by intravenous injection.

The compound of the present invention can be used in combination with anadditional drug. Specifically, the compound of the present invention canbe used in combination with a drug such as a hormone therapeutic, achemotherapeutic, an immunotherapeutic, an agent inhibiting the effectsof a cell growth factor and its receptor, or the like. Hereinafter, thedrug that may be used in combination with the compound of the presentinvention is referred to as a concomitant drug.

Examples of the “hormone therapeutic” that may be used includefosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesteroneacetate, megestrol acetate, chlormadinone acetate, cyproterone acetate,danazol, allylestrenol, gestrinone, mepartricin, raloxifene,ormeloxifene, levormeloxifene, anti-estrogen (e.g., tamoxifen citrate,toremifene citrate), contraceptive pills, mepitiostane, testololactone,aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin,leuprorelin acetate), droloxifene, epitiostanol, ethinyl estradiolsulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride,anastrozole, letrozole, exemestane, vorozole, formestane), anti-androgen(e.g., flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductaseinhibitors (e.g., finasteride, epristeride, dutasteride), adrenalcorticosteroid agents (e.g., dexamethasone, prednisolone, betamethasone,triamcinolone), androgen synthesis inhibitors (e.g., abiraterone),retinoid and agents delaying retinoid metabolism (e.g., liarozole),thyroid hormones and DDS (drug delivery system) preparations thereof.

Examples of the “chemotherapeutic” that may be used include analkylating agent, an antimetabolite, an anticancer antibiotic and aplant-derived anticancer agent.

Examples of the “alkylating agent” that may be used include nitrogenmustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil,cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosilate, busulfan, nimustine hydrochloride, mitobronitol, melphalan,dacarbazine, ranimustine, estramustine sodium phosphate,triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman,etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin,altretamine, ambamustine, dibrospidium hydrochloride, fotemustine,prednimustine, pumitepa, Ribomustin, temozolomide, treosulfan,trofosfamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesinand DDS preparations thereof.

Examples of the “antimetabolite” that may be used includemercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate,pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabinehydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT,doxifluridine, carmofur, galocitabine, emitefur, capecitabine),aminopterin, nelarabine, leucovorin calcium, tabloid, butocine, calciumfolinate, calcium levofolinate, cladribine, emitefur, fludarabine,gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine,mitoguazone, tiazofurin, ambamustine, bendamustine and DDS preparationsthereof.

Examples of the “anticancer antibiotic” that may be used includeactinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycinhydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicinhydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride,pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin,mithramycin, sarkomycin, carzinophilin, mitotane, zorubicinhydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride andDDS preparations (e.g., PEG liposomal doxorubicin) thereof.

Examples of the “plant-derived anticancer agent” that may be usedinclude etoposide, etoposide phosphate, vinblastine sulfate, vincristinesulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel,cabazitaxel, vinorelbine and DDS preparations thereof.

Examples of the “immunotherapeutic” that may be used include picibanil,Krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin,macrophage colony-stimulating factor, granulocyte colony-stimulatingfactor, erythropoietin, lymphotoxin, BCG vaccines, Corynebacteriumparvum, levamisole, polysaccharide K, procodazol, anti-CTLA4 antibodies(e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab,pembrolizumab) and anti-PD-LI antibodies.

The “cell growth factor” in the “agent inhibiting the effects of a cellgrowth factor and its receptor” can be any substance that promotes thegrowth of cells. Typical examples thereof include a factor that is apeptide having a molecular weight of 20,000 or smaller and exerts itseffects at a low concentration through binding to its receptor. Specificexamples of the cell growth factor that may be used include (1) EGF(epidermal growth factor) or a substance having activity substantiallyidentical thereto [e.g., TGFα], (2) insulin or a substance havingactivity substantially identical thereto [e.g., insulin, IGF(insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growthfactor) or a substance having activity substantially identical thereto[e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10],and (4) other cell growth factors [e.g., CSF (colony stimulatingfactor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growthfactor), PDGF (platelet-derived growth factor), TGFβ (transforminggrowth factor β), HGF (hepatocyte growth factor), VEGF (vascularendothelial growth factor), heregulin, angiopoietin].

The “receptor of the cell growth factor” can be any receptor having theability to bind to any of the cell growth factor described above.Specific examples of the receptor that may be used include EGF receptor,heregulin receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGFreceptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor,angiopoietin receptor (e.g., Tie2), PDGF receptor and the like.

Examples of the “agent inhibiting the effects of a cell growth factorand its receptor” that may be used include EGF inhibitors, TGFαinhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors,FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGFinhibitors, VEGF inhibitors, angiopoietin inhibitors, EGF receptorinhibitors, HER2 inhibitors, HER4 inhibitors, insulin receptorinhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGFreceptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors,FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PKC inhibitors, Smoinhibitors, ALK inhibitors, ROR1 inhibitors, Trk inhibitors, Retinhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK(MEK1/2) inhibitors, MET inhibitors, CDK inhibitors, Akt inhibitors, ERKinhibitors, PI3K inhibitors and the like. More specific examples of theagent that may be used include anti-VEGF antibodies (e.g., bevacizumab,ramucirumab), anti-HER2 antibodies (e.g., trastuzumab, pertuzumab),anti-EGFR antibodies (e.g., cetuximab, panitumumab, matuzumab,nimotuzumab), anti-HGF antibodies, imatinib, erlotinib, gefitinib,sorafenib, sunitinib, dasatinib, lapatinib, vatalanib, ibrutinib,bosutinib, cabozantinib, crizotinib, alectinib, vismodegib, axitinib,motesanib, nilotinib,6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(AEE-788), vandetanib, temsirolimus, everolimus, enzastaurin,tozasertib, phosphoric acid2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethylester (AZD-1152),4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazapin-2-ylamino]benzoicacid, N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycine sodium salt (ON-1910Na), volasertib,selumetinib, trametinib,N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide(PD-0325901), bosutinib, regorafenib, afatinib, idelalisib, ceritinib,dabrafenib and the like.

In addition to the drugs described above, examples that may be used asthe concomitant drug also include L-asparaginase, L-arginase, argininedeiminase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobaltcomplex salt, mercury hematoporphyrin-sodium, topoisomerase I inhibitors(e.g., irinotecan, topotecan, indotecan, indimitecan), topoisomerase IIinhibitors (e.g., sobuzoxane), differentiation inducers (e.g., retinoid,vitamins D), other angiogenesis inhibitors (e.g., fumagillin, sharkextracts, COX-2 inhibitors), α-blockers (e.g., tamsulosinhydrochloride), bisphosphonic acids (e.g., pamidronate, zoledronate),thalidomide, lenalidomide, pomalidomide, 5-azacytidine, decitabine,proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib), NEDD8inhibitors (e.g., pevonedistat), UAE inhibitors, PARP inhibitors (e.g.,olaparib, niraparib, veliparib), antitumor antibodies such as anti-CD20antibodies (e.g., rituximab, obinutuzumab), anti-CCR4 antibodies (e.g.,mogamulizumab) and the like, antibody-drug conjugates (e.g., trastuzumabemtansine, brentuximab vedotin), MDM2 inhibitors or the like.

The combination of the compound of the present invention and theconcomitant drug can produce excellent effects such as: (1) the dose ofthe compound of the present invention or the concomitant drug can bereduced as compared with the administration of the compound of thepresent invention or the concomitant drug alone; (2) the concomitantdrug can be selected for combined use with the compound of the presentinvention according to the symptoms (mild, serious, etc.) of a patient;(3) the period of treatment can be set longer; (4) a sustainedtherapeutic effect can be achieved; (5) a synergistic effect can beobtained by the combined use of the compound of the present inventionand the concomitant drug; and the like.

Hereinafter, the combined use of the compound of the present inventionand the concomitant drug is referred to as the “combination drug of thepresent invention”.

For use of the combination drug of the present invention, the time ofadministration of the compound of the present invention and the time ofadministration of the concomitant drug are not limited, and the compoundof the present invention and the concomitant drug may be administeredsimultaneously or in a staggered manner to a recipient. In the case ofadministration in a staggered manner, the staggered manner differsdepending on active ingredients to be administered, a dosage form and anadministration method. In the case of first administering, for example,the concomitant drug, the compound of the present invention can beadministered within 1 minute to 3 days, preferably within 10 minutes to1 day, more preferably within 15 minutes to 1 hour, after theadministration of the concomitant drug. In the case of firstadministering the compound of the present invention, the concomitantdrug can be administered within 1 minute to 1 day, preferably within 10minutes to 6 hours, more preferably within 15 minutes to 1 hour, afterthe administration of the compound of the present invention. The dose ofthe concomitant drug can abide by a dose clinically used and can beappropriately selected according to a recipient, an administrationroute, a disease, a combination, etc.

Examples of the administration mode of the compound of the presentinvention and the concomitant drug used in combination include (1) theadministration of a single preparation obtained by simultaneouslyformulating the compound of the present invention and the concomitantdrug, (2) the simultaneous administration through the sameadministration route of two preparations obtained by separatelyformulating the compound of the present invention and the concomitantdrug, (3) the administration through the same administration route in astaggered manner of two preparations obtained by separately formulatingthe compound of the present invention and the concomitant drug, (4) thesimultaneous administration through different administration routes oftwo preparations obtained by separately formulating the compound of thepresent invention and the concomitant drug, and (5) the administrationthrough different administration routes in a staggered manner of twopreparations obtained by separately formulating the compound of thepresent invention and the concomitant drug (e.g., administration in theorder of the compound of the present invention and then the concomitantdrug, or in the reverse order).

The dose of the concomitant drug can be appropriately selected on thebasis of a dose clinically used. The mixing ratio between the compoundof the present invention and the concomitant drug can be appropriatelyselected according to a recipient, an administration route, a targetdisease, symptoms, a combination, etc. When the recipient is, forexample, a human, 0.01 to 100 parts by weight of the concomitant drugcan be used with respect to 1 part by weight of the compound of thepresent invention.

The compound of the present invention or the combination drug of thepresent invention can be further used in combination with a non-drugtherapy. Specifically, the compound of the present invention or thecombination drug of the present invention may be combined with anon-drug therapy, for example, (1) surgery, (2) induced hypertensionchemotherapy using angiotensin II or the like, (3) gene therapy, (4)thermotherapy, (5) cryotherapy, (6) laser cauterization or (7)radiotherapy.

The compound of the present invention or the combination drug of thepresent invention is used, for example, before or after the surgery orthe like or before or after treatment involving two or three of thesetherapies in combination to produce effects such as prevention ofdevelopment of resistance, prolonged disease-free survival, inhibitionof cancer metastasis or recurrence, life prolongation and the like.

Also, the treatment with the compound of the present invention or thecombination drug of the present invention may be combined withsupportive care [(i) the administration of an antibiotic (e.g., aβ-lactam antibiotic such as Pansporin and the like, a macrolideantibiotic such as clarithromycin and the like) against variousintercurrent infections, (ii) the administration of a high-calorieinfusion, an amino acid preparation or multivitamin for the improvementof malnutrition, (iii) the administration of morphine for pain relief,(iv) the administration of a drug improving adverse reactions such asnausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia,decreased hemoglobin concentration, alopecia, liver damage, kidneydamage, DIC, fever and the like and (v) the administration of a drug forinhibiting multidrug resistance of cancer, etc.].

The present invention will be described further specifically withreference to Examples, Formulation Examples and Test Examples givenbelow. However, the present invention is not intended to be limited bythem, and various changes or modifications may be made therein withoutdeparting from the scope of the present invention.

EXAMPLES

In Examples below, the term “room temperature” usually meansapproximately 10° C. to approximately 35° C. A ratio used for a mixedsolvent represents a volume ratio unless otherwise specified. %represents % by weight unless otherwise specified.

In silica gel column chromatography, the term “NH” represents that anaminopropylsilane-bound silica gel was used, the term “Diol” representsthat a 3-(2,3-dihydroxypropoxy)propylsilane-bound silica gel, was used,and the term “DiNH” represents that anN-(2-aminoethyl)-3-aminopropylsilane-bound silica gel. In HPLC (HighSpeed Liquid Chromatography), the term “C18” represents that anoctadecyl-bound silica gel was used. A ratio used for elution solventsrepresents a volume ratio unless otherwise specified.

In Examples below, the following abbreviations are used:

mp: melting pointMS: mass spectrum[M+H]⁺, [M−H]⁻: molecular ion peakM: molar concentrationN: normalityCDCl₃: deuterated chloroformDMSO-d₆: deuterated dimethyl sulfoxide¹H NMR: proton nuclear magnetic resonanceLC/MS: liquid chromatograph-mass spectrometerESI: electrospray ionizationAPCI: atmospheric pressure chemical ionizationTHF: tetrahydrofuranDME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide DMA: N,N-dimethylacetamide

DMSO: dimethyl sulfoxideHATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateHOBt: 1-hydroxybenzotriazoleCDI: 1,1′-carbonyldiimidazolePy: pyridineIPE: diisopropyl etherDIPEA: N,N′-diisopropylethylamineDMAP: N,N-dimethyl-4-aminopyridineIPA: isopropanolIPE: diisopropyl etherKHMDS: potassium bis(trimethylsilyl)amideDIPA: diisopropylamine

NBS: N-bromosuccinimide NMO: N-methylmorpholine N-oxide

TBAF: tetra-n-butylammonium fluoridepTsCl: p-toluenesulfonyl chlorideTFA: trifluoroacetic acidDIAD: diisopropyl azodicarboxylateCPME: cyclopentyl methyl etherEDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimideTLC: thin layer chromatographyIBX: 2-iodoxybenzoic acidTBAI: tetrabutylammonium iodideDIBAL: diisobutylaluminium hydrideAIBN: 2,2′-(E)-diazene-1,2-diylbis(2-methylpropanenitrile)

¹H NMR was measured by Fourier transform NMR. ACD/SpecManager (tradename) or the like was used in analysis. No mention was made about thevery broad peaks of protons of a hydroxy group, an amino group and thelike.

MS was measured by LC/MS. ESI or APCI was used as an ionization method.Data was indicated by actually measured values (found). In general,molecular ion peaks ([M+H]⁺, [M−H]⁻ and the like) are observed. Forexample, in the case of a compound having a tert-butoxycarbonyl group, afragment ion peak derived from the elimination of thetert-butoxycarbonyl group or the tert-butyl group is observed. In thecase of a compound having a hydroxy group, a fragment ion peak derivedfrom the elimination of H₂O may be observed. In the case of a salt, amolecular ion peak or fragment ion peak of a free form is usuallyobserved.

The unit of the sample concentration (c) in optical rotation (([α]D) isg/100 mL.

For the value of element analysis (Anal.), the calculated values (Calcd)and measured values (Found) are described.

Example 12-(azetidin-1-yl)-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea) 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine

4-chloro-5H-pyrrolo[3,2-d]pyrimidine (10 g) was suspended in methanol(50 mL), and sodium methoxide (28% methanol solution) (30 mL) was addedat room temperature. Under a dry atmosphere, the mixture was stirred at60° C. overnight. The reaction mixture was concentrated under reducedpressure. The residue was sequentially washed with water and IPA, andthen dried under reduced pressure to obtain the title compound (6.44 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.07 (3H, s), 6.54 (1H, d, J=3.0 Hz), 7.65(1H, d, J=3.0 Hz), 8.40 (1H, s), 12.01 (1H, brs).

b) 5-bromo-N3-(3,5-difluorobenzyl)pyridine-2,3-diamine

Acetic acid (5 mL) was added to a solution of 3,5-difluorobenzaldehyde(26.5 g) and 5-bromopyridine-2,3-diamine (25 g) in THF (400 mL) at roomtemperature. Under a dry atmosphere, the mixture was stirred at roomtemperature for 10 hours. The mixture was neutralized with saturatedaqueous sodium hydrogen carbonate solution at 0° C., and extracted withethyl acetate (250 mL)/toluene (250 mL). The organic layer was washedwith water and a saturated brine, dried over magnesium sulfate, and thenconcentrated to obtain a residue. Sodium borohydride (10.06 g) wassuspended in THF (200 mL), methanol (200 mL) was added at 0° C., and themixture was stirred for 10 minutes. The obtained suspension of theresidue in THF (300 mL) was added to the reaction mixture at 0° C. Undera dry atmosphere, the mixture was stirred at room temperature for 2hours. The reaction mixture was poured into ice water at 0° C., andextracted with ethyl acetate. The organic layer was sequentially washedwith water and a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (10 g).

¹H NMR (300 MHz, DMSO-d₆) δ4.35 (2H, d, J=5.8 Hz), 5.71-5.86 (3H, m),6.56 (1H, d, J=2.1 Hz), 7.03-7.16 (3H, m), 7.32 (1H, d, J=2.1 Hz).

c) 6-bromo-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

Under a dry atmosphere, a mixture of5-bromo-N3-(3,5-difluorobenzyl)pyridine-2,3-diamine (6 g), CDI (6.19 g)and THF (60 mL) was stirred at 60° C. for 16 hours. The reaction mixturewas diluted with water at room temperature, and extracted with ethylacetate. The organic layer was sequentially washed with a saturatedbrine, then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was washed with ethyl acetate/IPE to obtain thetitle compound (6.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.04 (2H, s), 7.03-7.23 (3H, m), 7.79 (1H,d, J=2.1 Hz), 8.03 (1H, d, J=2.0 Hz), 11.97 (1H, brs).

d) 6-bromo-2-chloro-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (6.4g) and phosphorus oxychloride (45 mL) was stirred under a nitrogenatmosphere at 100° C. for 22 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with THF,neutralized with a saturated aqueous sodium hydrogen carbonate solutionat 0° C., and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was washed with ethyl acetate/IPE to obtainthe title compound (4.59 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.59 (2H, s), 7.00 (2H, dd, J=8.3, 2.2 Hz),7.22 (1H, tt, J=9.4, 2.2 Hz), 8.55 (2H, q, J=2.1 Hz).

e)2-(azetidin-1-yl)-6-bromo-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-chloro-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridine (1.00g), azetidine (0.8 mL) and THF (8 mL) was stirred under a dry atmosphereat room temperature for 16 hours. The reaction mixture was diluted withwater at room temperature, and extracted with ethyl acetate. The organiclayer was washed with a saturated brine, dried over magnesium sulfate,and then concentrated. The residue was washed with ethyl acetate toobtain the title compound (0.946 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (2H, quin, J=7.6 Hz), 4.19 (4H, t,J=7.6 Hz), 5.31 (2H, s), 6.79-6.90 (2H, m), 7.18 (1H, tt, J=9.4, 2.3Hz), 7.86 (1H, d, J=2.2 Hz), 8.16 (1H, d, J=2.2 Hz).

f)2-(azetidin-1-yl)-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-(azetidin-1-yl)-6-bromo-1-(3,5-difluorobenzyl)-1H-imidazo[4,5-b]pyridine(200 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (157 mg), sodiumt-butoxide (101 mg), tris(dibenzylideneacetone)dipalladium (0) (33.8mg), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (62.7 mg)and toluene (5 mL) was stirred under microwave irradiation at 130° C.for 2 hours. The mixture was diluted with water/methanol at roomtemperature, and extracted with ethyl acetate/THF. The organic layer waswashed with a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate), and the residue was washed withethyl acetate to obtain the title compound (16.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.36 (2H, quin, J=7.6 Hz), 3.74 (3H, s),4.22 (4H, t, J=7.6 Hz), 5.32 (2H, s), 6.77 (1H, d, J=3.2 Hz), 6.86-6.94(2H, m), 7.20 (1H, tt, J=9.4, 2.3 Hz), 7.87 (2H, dd, J=2.8, 1.7 Hz),8.27 (1H, d, J=2.4 Hz), 8.48 (1H, s).

Example 71-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-H-imidazo[4,5-b]pyridinea) N3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 3,5-difluorobenzaldehyde (14.4 g),5-iodopyridine-2,3-diamine (15.4 g), acetic acid (10 mL) and THF (200mL) was stirred under nitrogen atmosphere at room temperature for 13hours. The reaction mixture was concentrated under reduced pressure. Theresidue was neutralized with a saturated aqueous sodium hydrogencarbonate solution at 0° C., and extracted with ethyl acetate/THF. Theorganic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over magnesium sulfate,and then concentrated to obtain a residue. Methanol (100 mL) was addedto a mixture of sodium borohydride (6.6 g) and THF (200 mL) at 0° C. Theobtained solution of the residue in THF (300 mL) was added to thereaction mixture at 0° C. Under a nitrogen atmosphere, the mixture wasstirred at room temperature for 2 hours. Water and a saturated aqueousammonium chloride solution were added to the reaction mixture at 0° C.to stop the reaction, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (18.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (2H, d, J=5.9 Hz), 5.69 (1H, t, J=5.8Hz), 5.79 (2H, s), 6.65 (1H, d, J=1.8 Hz), 7.01-7.18 (3H, m), 7.42 (1H,d, J=1.8 Hz).

b) 1-(3,5-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (1 mL) was added to a mixture ofN3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (5 g) and trimethylorthoacetate (50 mL) at room temperature. The mixture was stirred undera dry atmosphere at room temperature for 2 hours. The mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solutionat room temperature, and extracted with ethyl acetate/THF. The organiclayer was washed with a saturated brine, then dried over magnesiumsulfate, and concentrated under reduced pressure. The residue was washedwith ethyl acetate to obtain the title compound (3.46 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (3H, s), 5.54 (2H, s), 6.80-6.92 (2H,m), 7.20 (1H, tt, J=9.4, 2.3 Hz), 8.39 (1H, d, J=1.9 Hz), 8.53 (1H, d,J=2.0 Hz).

c)1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3,5-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (1.1g), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (0.554 g), potassium phosphate(1.819 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.406 g), copper(I) iodide (0.272 g) and THF (26 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with waterat room temperature, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), and the residue wascrystallized from ethanol/IPE to obtain the title compound (0.916 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 3.73 (3H, s), 5.57 (2H, s),6.83 (1H, d, J 5=3.2 Hz), 6.88-6.97 (2H, m), 7.22 (1H, tt, J=9.4, 2.3Hz), 7.97 (1H, d, J=3.2 Hz), 8.29 (1H, d, J=2.4 Hz), 8.51 (1H, s), 8.55(1H, d, J=2.4 Hz).

Example 102-ethoxy-1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea) N3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 3-fluorobenzaldehyde (4.75 g), 5-iodopyridine-2,3-diamine(6 g), acetic acid (3.7 mL) and THF (80 mL) was stirred under a nitrogenatmosphere at room temperature for 3 days. The reaction mixture wasconcentrated under reduced pressure. The residue was neutralized with asaturated aqueous sodium hydrogen carbonate solution at 0° C., andextracted with ethyl acetate/THF. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedbrine, dried over magnesium sulfate, and then concentrated to obtain aresidue. Methanol (30 mL) was added to a mixture of sodium borohydride(2.83 g) and THF (80 mL) at 0° C. The obtained solution of the residuein THF (120 mL) was added to the reaction mixture at 0° C. Under anitrogen atmosphere, the mixture was stirred at room temperature for 2hours. Water and a saturated aqueous ammonium chloride solution wereadded to the reaction mixture at 0° C. to stop the reaction, and themixture was extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (4.61 g).

1H NMR (300 MHz, DMSO-d₆) δ 4.31 (2H, d, J=5.7 Hz), 5.67 (1H, t, J=5.7Hz), 5.79 (2H, s), 6.65 (1H, d, J=1.8 Hz), 7.03-7.12 (1H, m), 7.13-7.23(2H, m), 7.34-7.44 (2H, m).

b) 1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine-2(3H)-thione

Under a dry atmosphere, a mixture ofN3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (1.15 g),1,1′-thiocarbonyldiimidazole (1.31 g) and THF (15 mL) was stirred at 60°C. for 16 hours. The reaction mixture was quenched with water at roomtemperature, and extracted with ethyl acetate. The organic layer wassequentially washed with a saturated aqueous ammonium chloride solution,water and a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was washed with ethylacetate to obtain the title compound (1.26 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.49 (2H, s), 7.08-7.27 (3H, m), 7.39 (1H,td, J=7.9, 6.2 Hz), 8.09 (1H, d, J=1.7 Hz), 8.36 (1H, d, J=1.7 Hz),13.69 (1H, brs).

c) 2-ethoxy-1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine

To a mixture of1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine-2(3H)-thione (1.25g) and DMF (2 mL) was added thionyl chloride (5 mL). Under a dryatmosphere, the mixture was stirred at 70° C. for 30 minutes. Thereaction mixture was concentrated under reduced pressure. The residuewas neutralized with a saturated aqueous sodium hydrogen carbonatesolution at 0° C., and extracted with ethyl acetate/THF. The organiclayer was washed with a saturated brine, then dried over magnesiumsulfate, and concentrated under reduced pressure. The residue wassuspended in ethanol (5 mL)/THF (5 mL), and sodium ethoxide (21% ethanolsolution) (7 mL) was added at room temperature. Under a dry atmosphere,the mixture was stirred at room temperature for 1 hour. The mixture wasdiluted with water at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane), and washed with IPE to obtain the title compound (0.498g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.39 (3H, t, J=7.0 Hz), 4.61 (2H, q, J=7.1Hz), 5.27 (2H, s), 7.06 (1H, d, J=7.8 Hz), 7.10-7.18 (2H, m), 7.34-7.46(1H, m), 8.22 (1H, d, J=1.9 Hz), 8.38 (1H, d, J=1.9 Hz).

d)2-ethoxy-1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-ethoxy-1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine (300 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (146 mg), potassium phosphate (481mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (107 mg), copper (I)iodide (71.9 mg) and THF (4 mL) was stirred under microwave irradiationat 110° C. for 2 hours. The mixture was diluted with water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate), and the residue was washed withethyl acetate to obtain the title compound (37.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.44 (3H, t, J=7.0 Hz), 3.73 (3H, s), 4.67(2H, q, J=7.1 Hz), 5.29 (2H, s), 6.81 (1H, d, J=3.2 Hz), 7.10-7.24 (3H,m), 7.37-7.49 (1H, m), 7.92 (1H, d, J=3.2 Hz), 8.16 (1H, d, J=2.4 Hz),8.38 (1H, d, J=2.3 Hz), 8.50 (1H, s).

Example 121-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) 1-(3-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (0.5 mL) was added to a mixture ofN3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (1.5 g) and trimethylorthoacetate (20 mL) at room temperature. The mixture was stirred undera dry atmosphere at room temperature for 2 hours. The mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solutionat room temperature, and extracted with ethyl acetate/THF. The organiclayer was washed with a saturated brine, then dried over magnesiumsulfate, and concentrated under reduced pressure. The residue was washedwith ethyl acetate to obtain the title compound (1.31 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.54 (2H, s), 6.91 (1H, d,J=7.6 Hz), 7.02 (1H, dt, J=9.9, 2.0 Hz), 7.14 (1H, td, J=8.5, 2.2 Hz),7.39 (1H, td, J=8.0, 6.1 Hz), 8.39 (1H, d, J=1.9 Hz), 8.52 (1H, d, J=1.9Hz).

b)1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (320 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (169 mg), potassium phosphate (555mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (124 mg), copper (I)iodide (83 mg) and THF (5 mL) was stirred under microwave irradiation at110° C. for 2 hours. The mixture was diluted with water and a 28%aqueous ammonia solution at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theresidue was washed with ethyl acetate to obtain the title compound (176mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.71 (3H, s), 5.57 (2H, s),6.83 (1H, d, J=3.2 Hz), 6.99 (1H, d, J=7.7 Hz), 7.07 (1H, dt, J=9.9, 2.0Hz), 7.16 (1H, td, J=8.5, 2.2 Hz), 7.42 (1H, td, J=7.9, 6.1 Hz), 7.96(1H, d, J=3.2 Hz), 8.28 (1H, d, J=2.4 Hz), 8.51 (1H, s), 8.54 (1H, d,J=2.4 Hz).

Example 13(1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanola) (1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol

A mixture of N3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (1.5 g),2-hydroxyacetic acid (8.31 g) and THF (3 mL) was heated under microwaveirradiation at 150° C. for 2 hours. The reaction mixture was poured intoa saturated aqueous sodium hydrogen carbonate solution, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (1.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.76 (2H, d, J=5.9 Hz), 5.61 (2H, s),5.84-5.92 (1H, m), 7.00-7.18 (3H, m), 7.34-7.43 (1H, m), 8.31 (1H, d,J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz).

b)(1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol

A mixture of(1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol (959mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (485 mg), potassium phosphate(1594 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (356 mg), copper(1) iodide (238 mg) and THF (13 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with waterand a 28% aqueous ammonia solution at room temperature, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (methanol/ethylacetate), and the residue was washed with ethyl acetate/ethanol toobtain the title compound (153 mg).

¹H NMR (300 MHz, DMSO-d₆) δ3.65 (3H, s), 4.83 (2H, d, J=5.6 Hz), 5.64(2H, s), 5.93 (1H, t, J=5.6 Hz), 6.83 (1H, d, J=3.2 Hz), 7.07-7.21 (3H,m), 7.36-7.47 (1H, m), 7.96 (1H, d, J=3.2 Hz), 8.22 (1H, d, J=2.2 Hz),8.50 (1H, s), 8.59 (1H, d, J=2.2 Hz).

Example 171-(3,4-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(3,4-difluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 3,4-difluorobenzaldehyde (7 g), 5-iodopyridine-2,3-diamine(7.3 g), acetic acid (5 mL) and THF (100 mL) was stirred under nitrogenatmosphere at room temperature for 13 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was neutralized with asaturated aqueous sodium hydrogen carbonate solution at 0° C., andextracted with ethyl acetate/THF. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution and a saturatedbrine, dried over magnesium sulfate, and then concentrated to obtain aresidue. Methanol (50 mL) was added to a mixture of sodium borohydride(2.9 g) and THF (100 mL) at 0° C. The obtained solution of the residuein THF (50 mL) was added to the reaction mixture at 0° C. Under anitrogen atmosphere, the mixture was stirred at room temperature for 2hours. A saturated aqueous ammonium chloride solution was added to thereaction mixture at 0° C. to stop the reaction, and the mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (8g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.28 (2H, d, J=5.7 Hz), 5.64 (1H, t, J=5.7Hz), 5.78 (2H, s), 6.66 (1H, d, J=1.8 Hz), 7.15-7.25 (1H, m), 7.33-7.48(3H, m).

b) 1-(3,4-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (300 μL) was added to a mixture ofN3-(3,4-difluorobenzyl)-5-iodopyridine-2,3-diamine (1.1 g) and trimethylorthoacetate (5 mL) at room temperature. The mixture was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure. The residue was washed with IPE to obtain the titlecompound (790 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (3H, s), 5.50 (2H, s), 6.89-7.02 (1H,m), 7.25-7.50 (2H, m), 8.40 (1H, d, J=1.9 Hz), 8.52 (1H, d, J=2.0 Hz).

c)1-(3,4-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3,4-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (202.7mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (78 mg), potassium phosphate(335 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (90 mg), copper (I)iodide (60.1 mg) and THF (2 mL) was stirred under microwave irradiationat 150° C. for 3 hours. The mixture was cooled to room temperature, andinsolubles were removed. The mixture was concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate), and crystallized from ethanolto obtain the title compound (66 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 3.74 (3H, s), 5.53 (2H, s),6.83 (1H, d, J=3.2 Hz), 6.96-7.09 (1H, m), 7.31-7.51 (2H, m), 7.96 (1H,d, J=3.2 Hz), 8.29 (1H, d, J=2.4 Hz), 8.46-8.58 (2H, m).

Example 201-(2,3-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(2,3-difluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 2,3-difluorobenzaldehyde (13.6 g),5-iodopyridine-2,3-diamine (15 g), acetic acid (7.31 mL) and THF (100mL) was stirred under nitrogen atmosphere at room temperature for 13hours. The reaction mixture was concentrated under reduced pressure. Theresidue was neutralized with a saturated aqueous sodium hydrogencarbonate solution at 0° C., and extracted with ethyl acetate/THF. Theorganic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over magnesium sulfate,and then concentrated to obtain a residue. Methanol (50 mL) was added toa mixture of sodium borohydride (6.04 g) and THF (100 mL) at 0° C. Theobtained solution of the residue in THF (300 mL) was added to thereaction mixture at 0° C. Under a nitrogen atmosphere, the mixture wasstirred at room temperature for 2 hours. Water and a saturated aqueousammonium chloride solution were added to the reaction mixture at 0° C.to stop the reaction, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (14.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.36 (2H, d, J=5.6 Hz), 5.54-5.66 (1H, m),5.80 (2H, s), 6.72 (1H, d, J=1.6 Hz), 7.11-7.56 (4H, m).

b) 1-(2,3-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (300 μL) was added to a mixture ofN3-(2,3-difluorobenzyl)-5-iodopyridine-2,3-diamine (144.9 mg) andtrimethyl orthoacetate (3 mL) at room temperature. The mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (105 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 2.53 (3H, s), 5.64 (2H, s), 6.76 (1H, t,J=7.3 Hz), 7.13-7.22 (1H, m), 7.36-7.46 (1H, m), 8.40 (1H, d, J=2.0 Hz),8.52 (1H, d, J=2.0 Hz).

c)1-(2,3-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(2,3-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (105.1mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (44.8 mg), potassiumphosphate (174 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (46.6mg), copper (I) iodide (31.2 mg) and THF (2 mL) was stirred undermicrowave irradiation at 150° C. for 3 hours. The mixture was cooled toroom temperature, poured into water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by NH silica gel column chromatography (methanol/ethylacetate), and crystallized from ethanol/IPE to obtain the title compound(44.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.72 (3H, s), 5.67 (2H, s),6.77-6.85 (2H, m), 7.15-7.25 (1H, m), 7.36-7.48 (1H, m), 7.94 (1H, d,J=3.2 Hz), 8.26 (1H, d, J=2.4 Hz), 8.51 (1H, s), 8.55 (1H, d, J=2.4 Hz).

Example 211-benzyl-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-Benzyl-5-iodopyridine-2,3-diamine

Acetic acid (200 μL) was added to a solution of benzaldehyde (600 μL)and 5-iodopyridine-2,3-diamine (1.12 g) in THF (50 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Thereaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with water and a saturated brine, dried over magnesiumsulfate, and then concentrated. Sodium borohydride (0.27 g) was added toa solution of the residue in methanol (50 mL) at 0° C. The mixture wasstirred at 0° C. for 1 hour. The reaction mixture was poured into asaturated aqueous ammonium chloride solution, and extracted with ethylacetate. The organic layer was washed with water and a saturated brine,then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (1.13g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.28 (2H, d, J=5.6 Hz), 5.64 (1H, t, J=5.6Hz), 5.78 (2H, s), 6.65 (1H, d, J=1.8 Hz), 7.20-7.43 (6H, m).

b) 1-benzyl-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (0.1 mL) was added to a mixture ofN3-benzyl-5-iodopyridine-2,3-diamine (300 mg) and trimethyl orthoacetate(4 mL) at room temperature. The mixture was stirred under a dryatmosphere at room temperature for 1 hour. The mixture was neutralizedwith a saturated aqueous sodium hydrogen carbonate solution at roomtemperature, and extracted with ethyl acetate/THF. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was washed with ethylacetate/hexane to obtain the title compound (230 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.51 (2H, s), 7.05-7.17 (2H,m), 7.23-7.44 (3H, m), 8.38 (1H, d, J=1.9 Hz), 8.51 (1H, d, J=1.9 Hz).

c)1-benzyl-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of 1-benzyl-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (200mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (111 mg), potassium phosphate(365 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.09 mL), copper(I) iodide (54.5 mg) and THF (5 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with waterand a 28% aqueous ammonia solution at room temperature, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (methanol/ethylacetate), and the residue was crystallized from water/ethanol to obtainthe title compound (120 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.70 (3H, s), 5.55 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.13-7.24 (2H, m), 7.25-7.44 (3H, m), 7.96 (1H,d, J=3.2 Hz), 8.27 (1H, d, J=2.4 Hz), 8.50 (1H, s), 8.53 (1H, d, J=2.4Hz).

Example 221-(4-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(4-fluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 4-fluorobenzaldehyde (0.507 mL), 5-iodopyridine-2,3-diamine(1.03 g), THF (10 mL) and acetic acid (0.632 mL) was stirred overnightat room temperature. The reaction mixture was poured into a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. Sodium borohydride (0.415 g)was added to a solution of the residue in methanol (10 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Thereaction mixture was poured into water, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (1.21 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.26 (2H, d, J=5.5 Hz), 5.63 (1H, t, J=5.6Hz), 5.78 (2H, s), 6.65 (1H, d, J=1.8 Hz), 7.12-7.23 (2H, m), 7.34-7.43(3H, m).

b) 1-(4-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (0.1 mL) was added to a mixture ofN3-(4-fluorobenzyl)-5-iodopyridine-2,3-diamine (300 mg) and trimethylorthoacetate (4 mL) at room temperature. The mixture was stirred under adry atmosphere at room temperature for 1 hour. The mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solutionat room temperature, and extracted with ethyl acetate/THF. The organiclayer was washed with a saturated brine, then dried over magnesiumsulfate, and concentrated under reduced pressure. The residue was washedwith ethyl acetate to obtain the title compound (244 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.50 (2H, s), 7.13-7.25 (4H,m), 8.40 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.0 Hz).

c)1-(4-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(4-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (200 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (106 mg), potassium phosphate (347mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.086 mL), copper (I)iodide (51.9 mg) and THF (5 mL) was stirred under microwave irradiationat 110° C. for 2 hours. The mixture was diluted with water and a 28%aqueous ammonia solution at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theresidue was crystallized from water/ethanol to obtain the title compound(88 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.73 (3H, s), 5.53 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.10-7.38 (4H, m), 7.96 (1H, d, J=3.2 Hz), 8.29(1H, d, J=2.4 Hz), 8.51 (1H, s), 8.53 (1H, d, J=2.4 Hz).

Example 231-(2,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(2,5-difluorobenzyl)-5-iodopyridine-2,3-diamine

Acetic acid (200 μL) was added to a solution of 2,5-difluorobenzaldehyde(400 μL) and 5-iodopyridine-2,3-diamine (0.72 g) in THF (50 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Thereaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with water and a saturated brine, dried over magnesiumsulfate, and then concentrated. Sodium borohydride (0.174 g) was addedto a solution of the residue in methanol (50 mL) at 0° C. The mixturewas stirred at 0° C. for 1 hour. The reaction mixture was poured into asaturated aqueous ammonium chloride solution, and extracted with ethylacetate. The organic layer was washed with water and a saturated brine,then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (0.82g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.31 (2H, d, J=5.6 Hz), 5.56 (1H, t, J=5.6Hz), 5.80 (2H, s), 6.72 (1H, d, J=1.8 Hz), 7.07-7.35 (3H, m), 7.44 (1H,d, J=1.8 Hz).

b) 1-(2,5-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (0.1 mL) was added to a mixture ofN3-(2,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (300 mg) andtrimethyl orthoacetate (4 mL) at room temperature. The mixture wasstirred under a dry atmosphere at room temperature for 1 hour. Themixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution at room temperature, and extracted with ethylacetate/THF. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was washed with ethyl acetate to obtain the title compound(249 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.56 (2H, s), 6.85-7.03 (1H,m), 7.16-7.42 (2H, m), 8.30-8.58 (2H, m).

c)1-(2,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(2,5-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (200mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (101 mg), potassium phosphate(331 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.082 mL), copper(I) iodide (49.4 mg) and THF (5 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with waterand a 28% aqueous ammonia solution at room temperature, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (methanol/ethylacetate), and the residue was washed with ethyl acetate to obtain thetitle compound (131 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.72 (3H, s), 5.59 (2H, s),6.83 (1H, d, J=3.3 Hz), 6.91-7.02 (1H, m), 7.17-7.42 (2H, m), 7.94 (1H,d, J=3.3 Hz), 8.25 (1H, d, J=2.4 Hz), 8.51 (1H, s), 8.54 (1H, d, J=2.4Hz).

Example 241-(3-fluorobenzyl)-2-(methoxymethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea) 1-(3-fluorobenzyl)-6-iodo-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine

A mixture of N3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (251 mg),2-methoxyacetic acid (86 mg), THF (4 mL), propylphosphonic anhydride(50% in ethyl acetate solution) (0.58 mL) and DIPEA (0.35 mL) was heatedunder microwave irradiation at 200° C. for 2 hours. The mixture wasdiluted with a saturated aqueous sodium hydrogen carbonate solution atroom temperature, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (232mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (3H, s), 4.72 (2H, s), 5.58 (2H, s),6.98 (1H, d, J=7.7 Hz), 7.03-7.18 (2H, m), 7.39 (1H, td, J=8.0, 6.1 Hz),8.37 (1H, d, J=2.0 Hz), 8.60 (1H, d, J=1.9 Hz).

b)1-(3-fluorobenzyl)-2-(methoxymethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-iodo-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine(226 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (110 mg), potassiumphosphate (362 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (81 mg),copper (I) iodide (54.2 mg) and THF (4 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with waterand a 28% aqueous ammonia solution at room temperature, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (methanol/ethylacetate), and the residue was washed with ethyl acetate/IPE to obtainthe title compound (73.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.35 (3H, s), 3.68 (3H, s), 4.79 (2H, s),5.61 (2H, s), 6.84 (1H, d, J=3.1 Hz), 7.01-7.22 (3H, m), 7.35-7.47 (1H,m), 7.96 (1H, d, J=3.1 Hz), 8.28 (1H, d, J=2.1 Hz), 8.51 (1H, s), 8.63(1H, d, J=2.0 Hz).

Example 275-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-aminea)6-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyrimidine(155 mg) and phosphorus oxychloride (4.5 mL) was stirred under anitrogen atmosphere at 100° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was neutralized with asaturated aqueous sodium hydrogen carbonate solution at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate), and washed with ethyl acetate to obtainthe title compound (112 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.64 (3H, s), 5.57 (2H, s), 6.96-7.07 (3H,m), 7.14 (1H, td, J=8.5, 2.2 Hz), 7.39 (1H, td, J=8.0, 6.1 Hz), 8.24(1H, d, J=3.3 Hz), 8.37 (1H, d, J=2.3 Hz), 8.57 (1H, d, J=2.3 Hz), 8.75(1H, s).

b)5-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of6-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine(95 mg) and methylamine (2M in THF solution) (4 mL) was stirred undermicrowave irradiation at 120° C. for 3 hours. The mixture was purifiedby NH silica gel column chromatography (ethyl acetate), and washed withethyl acetate to obtain the title compound (42.7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H, s), 2.71 (3H, d, J=4.5 Hz), 5.47(1H, d, J=4.5 Hz), 5.57 (2H, s), 6.62 (1H, d, J=3.2 Hz), 7.04-7.19 (3H,m), 7.36-7.46 (1H, m), 7.68 (1H, d, J=3.2 Hz), 8.08 (1H, d, J=2.4 Hz),8.29 (1H, s), 8.54 (1H, d, J=2.4 Hz).

Example 281-(2-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(2-fluorobenzyl)-5-iodopyridine-2,3-diamine

Under a nitrogen atmosphere, a mixture of 2-fluorobenzaldehyde (0.792g), 5-iodopyridine-2,3-diamine (1 g), THF (100 mL) and acetic acid(0.487 mL) was stirred at room temperature for 13 hours. The reactionmixture was concentrated under reduced pressure. The residue wasneutralized with a saturated aqueous sodium hydrogen carbonate solutionat 0° C., and extracted with ethyl acetate/THF. The organic layer waswashed with a saturated aqueous sodium hydrogen carbonate solution and asaturated brine, dried over magnesium sulfate, and then concentrated toobtain a residue. Methanol (100 mL) was added to a mixture of sodiumborohydride (0.402 g) and THF (100 mL) at 0° C. The obtained solution ofthe residue in THF (300 mL) was added to the reaction mixture at 0° C.Under a nitrogen atmosphere, the mixture was stirred at room temperaturefor 2 hours. Water and a saturated aqueous ammonium chloride solutionwere added to the reaction mixture at 0° C. to stop the reaction, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (1.12 g).

¹H NMR (300 MHz, DMSO-d₆) δ4.30 (2H, d, J=5.5 Hz), 5.46-5.60 (1H, m),5.79 (2H, s), 6.70 (1H, d, J=1.8 Hz), 7.12-7.52 (5H, m).

b) 1-(2-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (300 μL) was added to a mixture ofN3-(2-fluorobenzyl)-5-iodopyridine-2,3-diamine (500 mg) and trimethylorthoacetate (5 mL) at room temperature. The mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure. The residue was washed with IPE to obtain the title compound(400 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.53 (3H, s), 5.57 (2H, s), 6.94-7.48 (4H,m), 8.37 (1H, d, J=1.6 Hz), 8.51 (1H, d, J=1.9 Hz).

c)1-(2-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(2-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (200 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (81 mg), potassium phosphate (347mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (93 mg), copper (I)iodide (62.2 mg) and THF (5 mL) was stirred under microwave irradiationat 110° C. for 2 hours. The mixture was cooled to room temperature, andinsolubles were removed. The mixture was concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate), and washed with ethanol toobtain the title compound (80 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.61 (3H, s), 3.71 (3H, s), 5.61 (2H, s),6.83 (1H, d, J 10=3.2 Hz), 7.00-7.47 (4H, m), 7.94 (1H, d, J=3.2 Hz),8.23 (1H, d, J=2.4 Hz), 8.46-8.58 (2H, m).

Example 311-(2,4-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(2,4-difluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 2,4-difluorobenzaldehyde (0.237 mL),5-iodopyridine-2,3-diamine (392.4 mg), THF (8 mL) and acetic acid (0.482mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.Sodium borohydride (158 mg) was added to a solution of the residue inmethanol (8 mL) at room temperature. The mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (493mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.27 (2H, d, J=5.5 Hz), 5.52 (1H, t, J=5.6Hz), 5.78 (2H, s), 6.71 (1H, d, J=1.8 Hz), 7.08 (1H, tdd, J=8.5, 2.6,0.9 Hz), 7.26 (1H, ddd, J=10.5, 9.4, 2.6 Hz), 7.36-7.47 (2H, m).

b) 1-(2,4-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture ofN3-(2,4-difluorobenzyl)-5-iodopyridine-2,3-diamine (492.8 mg) andtrimethyl orthoacetate (5 mL) at room temperature. The mixture wasstirred at 60° C. for 3 hours. The mixture was poured into a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (350 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.54 (2H, s), 7.02-7.21 (2H,m), 7.26-7.36 (1H, m), 8.38 (1H, d, J=1.9 Hz), 8.51 (1H, d, J=2.0 Hz).

c)1-(2,4-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(2,4-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (156.9mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (66.8 mg), potassiumphosphate (259 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (69.5mg), copper (I) iodide (46.6 mg) and THF (2.5 mL) was stirred undermicrowave irradiation at 150° C. for 3 hours. The mixture was cooled toroom temperature, then poured into a saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate), and crystallizedfrom ethanol and IPE to obtain the title compound (82 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.74 (3H, s), 5.58 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.04-7.24 (2H, m), 7.29-7.39 (1H, m), 7.94 (1H,d, J=3.2 Hz), 8.23 (1H, d, J=2.4 Hz), 8.51 (1H, s), 8.53 (1H, d, J=2.4Hz).

Example 321-(3-chlorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(3-chlorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 3-chlorobenzaldehyde (0.234 mL), 5-iodopyridine-2,3-diamine(374.1 mg), THF (8 mL) and acetic acid (0.23 mL) was stirred overnightat room temperature. The reaction mixture was poured into a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. Sodium borohydride (151 mg)was added to a solution of the residue in methanol (5 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Thereaction mixture was poured into water, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (394 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.30 (2H, d, J=5.7 Hz), 5.67 (1H, t, J=5.8Hz), 5.78 (2H, s), 6.65 (1H, d, J=1.8 Hz), 7.29-7.34 (2H, m), 7.35-7.44(3H, m).

b) 1-(3-chlorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture ofN3-(3-chlorobenzyl)-5-iodopyridine-2,3-diamine (393.8 mg) and trimethylorthoacetate (5 mL) at room temperature. The mixture was stirred at 60°C. for 3 hours. The mixture was cooled to room temperature, poured intoa saturated aqueous sodium hydrogen carbonate solution, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (298mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.53 (2H, s), 6.97-7.04 (1H,m), 7.24-7.27 (1H, m), 7.35-7.40 (2H, m), 8.40 (1H, d, J=2.0 Hz), 8.52(1H, d, J=1.9 Hz).

c)1-(3-chlorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-chlorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (129.3 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (52.8 mg), potassium phosphate(215 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (57.5 mg), copper(I) iodide (38.5 mg) and THF (2 mL) was stirred under microwaveirradiation at 150° C. for 3 hours. The mixture was cooled to roomtemperature, then poured into a saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), andcrystallized from ethanol/IPE to obtain the title compound (51.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.70 (3H, s), 5.57 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.05-7.12 (1H, m), 7.30 (1H, s), 7.35-7.45 (2H,m), 7.97 (1H, d, J=3.2 Hz), 8.28 (1H, d, J=2.3 Hz), 8.51 (1H, s), 8.55(1H, d, J=2.3 Hz).

Example 336-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1-(3-trifluoromethoxy)benzyl)-1H-imidazo[4,5-b]pyridine a) 5-iodo-N3-(3-(trifluoromethoxy)benzyl)pyridine-2,3-diamine

A mixture of 3-(trifluoromethoxy)benzaldehyde (0.336 mL),5-iodopyridine-2,3-diamine (425 mg), THF (10 mL) and acetic acid (0.261mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.Sodium borohydride (171 mg) was added to a solution of the residue inmethanol (5 mL) at room temperature. The mixture was stirred overnightat room temperature. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (673mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.35 (2H, d, J=5.7 Hz), 5.71 (1H, t, J=5.8Hz), 5.78 (2H, s), 6.66 (1H, d, J=1.9 Hz), 7.22-7.28 (1H, m), 7.34 (1H,s), 7.36-7.43 (2H, m), 7.45-7.53 (1H, m).

b)6-iodo-2-methyl-1-(3-(trifluoromethoxy)benzyl)-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture of5-iodo-N3-(3-(trifluoromethoxy)benzyl)pyridine-2,3-diamine (672.9 mg)and trimethyl orthoacetate (5 mL) at room temperature. The mixture wasstirred at room temperature for 1 hour. The mixture was concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (458mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.58 (2H, s), 7.06 (1H, d,J=7.8 Hz), 7.25 (1H, s), 7.28-7.35 (1H, m), 7.44-7.52 (1H, m), 8.39 (1H,d, J=1.9 Hz), 8.52 (1H, d, J=1.9 Hz).

c)6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1-(3-trifluoromethoxy)benzyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-(3-(trifuoromethoxy)benzyl)-1H-imidazo[4,5-b]pyridine(137.5 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (49.7 mg), potassiumphosphate (202 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (54.2mg), copper (I) iodide (36.3 mg) and THF (2 mL) was stirred undermicrowave irradiation at 150° C. for 3 hours. The mixture was cooled toroom temperature, then poured into a saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) andcrystallized from ethanol/IPE to obtain the title compound (58.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.68 (3H, s), 5.62 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.11 (1H, d, J=7.9 Hz), 7.26-7.37 (2H, m),7.46-7.55 (1H, m), 7.95 (1H, d, J=3.4 Hz), 8.28 (1H, d, J=2.3 Hz), 8.50(1H, s), 8.55 (1H, d, J=2.4 Hz).

Example 346-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1-(3-trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridinea) 5-iodo-N3-(3-(trifluoromethyl)benzyl)pyridine-2,3-diamine

A mixture of 3-(trifluoromethyl)benzaldehyde (0.319 mL),5-iodopyridine-2,3-diamine (431 mg), THF (8 mL) and acetic acid (0.264mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.Sodium borohydride (173 mg) was added to a solution of the residue inmethanol (8 mL) at room temperature. The mixture was stirred overnightat room temperature. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (539mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.39 (2H, d, J=5.7 Hz), 5.71 (1H, t, J=5.8Hz), 5.79 (2H, s), 6.69 (1H, d, J=1.9 Hz), 7.41 (1H, d, J=1.9 Hz),7.55-7.69 (3H, m), 7.72 (1H, s).

b)6-iodo-2-methyl-1-(3-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture of5-iodo-N3-(3-(trifluoromethyl)benzyl)pyridine-2,3-diamine (538.5 mg) andtrimethyl orthoacetate (5 mL) at room temperature. The mixture wasstirred at 60° C. for 3 hours. The reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (397 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.63 (2H, s), 7.28 (1H, d,J=7.7 Hz), 7.53-7.61 (1H, m), 7.63 (1H, s), 7.65-7.71 (1H, m), 8.41 (1H,d, J=1.9 Hz), 8.52 (1H, d, J=2.0 Hz).

c)6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1-(3-trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-(3-(trifuoromethyl)benzyl)-1H-imidazo[4,5-b]pyridine(140.5 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (52.7 mg), potassiumphosphate (214 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (57.5mg), copper (I) iodide (38.5 mg) and THF (2 mL) was stirred undermicrowave irradiation at 150° C. for 2.5 hours. The mixture was cooledto room temperature, then poured into a saturated aqueous ammoniumchloride solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, then dried over magnesium sulfate,and concentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) andcrystallized from ethanol/IPE to obtain the title compound (67 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.64 (3H, s), 5.67 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.34 (1H, d, J=7.7 Hz), 7.56-7.73 (3H, m), 7.95(1H, d, J=3.2 Hz), 8.29 (1H, d, J=2.4 Hz), 8.50 (1H, s), 8.55 (1H, d,J=2.3 Hz).

Example 351-(2,6-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(2,6-difluorobenzyl)-5-iodopyridine-2,3-diamine

Acetic acid (300 μL) was added to a solution of 2,6-difluorobenzaldehyde(500 μL) and 5-iodopyridine-2,3-diamine (0.7 g) in THF (50 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Thereaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with water and a saturated brine, dried over magnesiumsulfate, and then concentrated. Sodium borohydride (0.169 g) was addedto a solution of the residue in methanol (50 mL) at 0° C. The mixturewas stirred at 0° C. for 1 hour. The reaction mixture was poured into anaqueous ammonium chloride solution, and extracted with ethyl acetate.The organic layer was washed with water and a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (0.263 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.24 (2H, d, J=5.1 Hz), 5.33 (1H, t, J=5.1Hz), 5.78 (2H, s), 6.89 (1H, d, J=1.8 Hz), 7.05-7.26 (2H, m), 7.35-7.55(2H, m).

b) 1-(2,6-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (0.1 mL) was added to a mixture ofN3-(2,6-difluorobenzyl)-5-iodopyridine-2,3-diamine (262.8 mg) andtrimethyl orthoacetate (4 mL) at room temperature. Under a dryatmosphere, the mixture was stirred at room temperature for 1 hour. Thereaction mixture was neutralized with a saturated aqueous sodiumhydrogen carbonate solution at room temperature, and extracted withethyl acetate/THF. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waswashed with ethyl acetate to obtain the title compound (200 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.58 (2H, s), 7.09-7.26 (2H,m), 7.39-7.58 (1H, m), 8.26-8.34 (1H, m), 8.50 (1H, d, J=2.0 Hz).

c)1-(2,6-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(2,6-difluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (200mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (101 mg), potassium phosphate(331 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.082 mL), copper(I) iodide (49.4 mg) and THF (5 mL) was stirred under microwaveirradiation at 110° C. for 2 hours. The mixture was diluted with anaqueous ammonia solution at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate), and washed with ethyl acetate to obtain thetitle compound (68.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.79 (3H, s), 5.62 (2H, s),6.84 (1H, d, J=3.2 Hz), 7.12-7.26 (2H, m), 7.43-7.58 (1H, m), 7.93 (1H,d, J=3.2 Hz), 8.10 (1H, d, J=2.4 Hz), 8.44-8.60 (2H, m).

Example 381-(3,5-difluorobenzyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea)1-(3,5-difluorobenzyl)-6-iodo-2-(isopropylthio)-1H-imidazo[4,5-b]pyridine

Under a dry atmosphere, a mixture ofN3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (5 g), CDI (4.5 g)and THF (50 mL) was stirred at 60° C. for 16 hours. The reaction mixturewas quenched with water at room temperature, and extracted with ethylacetate. The organic layer was sequentially washed with a saturatedaqueous ammonium chloride solution, water and a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure toobtain a white solid as1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one. Amixture of the obtained solid and phosphorus oxychloride (50 mL) wasstirred at 100° C. for 2 days. The reaction mixture was concentratedunder reduced pressure. The residue was diluted with THF, poured into asaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The organic layer was washed with water and a saturatedbrine, dried over sodium sulfate, and then concentrated. The residue wasdiluted with THF (100 mL). To the mixture was added sodium2-propanethiolate (1.963 g) at 0° C. Under a nitrogen atmosphere, themixture was stirred at room temperature for 1 hour. The reaction mixturewas poured into water, and extracted with ethyl acetate. The organiclayer was washed with water and a saturated brine, dried over sodiumsulfate, and then concentrated. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (5.73 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.45 (6H, d, J=6.8 Hz), 4.05-4.17 (1H, m),5.43 (2H, s), 6.87 (2H, dd, J=8.4, 2.2 Hz), 7.14-7.28 (1H, m), 8.42 (1H,d, J=2.0 Hz), 8.52 (1H, d, J=1.9 Hz).

b)1-(3,5-difluorobenzyl)-2-(isopropylthio)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of1-(3,5-difluorobenzyl)-6-iodo-2-(isopropylthio)-1H-imidazo[4,5-b]pyridine(203 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (88 mg), potassiumphosphate (290 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.144mL), copper (I) iodide (87 mg) and THF (5 mL) was stirred undermicrowave irradiation at 100° C. for 2 hours. The mixture was dilutedwith water and an aqueous ammonia solution at room temperature, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), and washed with ethyl acetateto obtain the title compound (170 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.49 (6H, d, J=6.8 Hz), 3.75 (3H, s),4.10-4.25 (1H, m), 5.46 (2H, s), 6.84 (1H, d, J=3.3 Hz), 6.90-7.02 (2H,m), 7.18-7.30 (1H, m), 7.97 (1H, d, J=3.2 Hz), 8.33 (1H, d, J=2.4 Hz),8.52 (1H, s), 8.55 (1H, d, J=2.4 Hz).

c)1-(3,5-difluorobenzyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

m-Chloroperbenzoic acid (55.5 mg) was added to a solution of1-(3,5-difluorobenzyl)-2-(isopropylthio)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine(60 mg) in acetonitrile (5 mL) at 0° C. The mixture was stirred for 10minutes, and then added to a solution of sodium methoxide (20 mg) inacetonitrile (5 mL) at 0° C. The mixture was stirred under a nitrogenatmosphere at room temperature for 5 hours. The reaction mixture waspoured into a saturated aqueous ammonium chloride solution at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with water and a saturated brine, dried over magnesium sulfate,and then concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (47mg).

¹H NMR (300 MHz, DMSO-d₆) δ3.74 (3H, s), 4.24 (3H, s), 5.30 (2H, s),6.82 (1H, d, J=3.2 Hz), 7.02-7.09 (2H, m), 7.15-7.29 (1H, m), 7.93 (1H,d, J=3.2 Hz), 8.18 (1H, d, J=2.4 Hz), 8.41 (1H, d, J=2.4 Hz), 8.51 (1H,s).

Example 391-(3-fluorobenzyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea) 1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one

Under a dry atmosphere, a mixture ofN3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (2.56 g), CDI (2.5 g) andTHF (30 mL) was stirred at 60° C. for 16 hours. The mixture was quenchedwith water at room temperature, and diluted with ethyl acetate. Theorganic layer was sequentially washed with a saturated aqueous ammoniumchloride solution, water and a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas washed with ethyl acetate to obtain the title compound (2.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ5.02 (2H, s), 7.08-7.22 (3H, m), 7.39 (1H,td, J=7.9, 6.1 Hz), 7.80 (1H, d, J=1.8 Hz), 8.12 (1H, d, J=1.8 Hz),11.87 (1H, s).

b) 2-chloro-1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine

A mixture of 1-(3-fluorobenzyl)-6-iodo-H-imidazo[4,5-b]pyridin-2(3H)-one(2.39 g) and phosphorus oxychloride (20 mL) was stirred under a nitrogenatmosphere at 100° C. for 18 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with THF,neutralized with a saturated aqueous sodium hydrogen carbonate solutionat room temperature, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was washed with ethyl acetate/IPE toobtain the title compound (1.78 g).

MS: [M+H]⁺ 388.1.

c)2-chloro-1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-chloro-1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine (300 mg),4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (150 mg), potassium phosphate (493mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.122 mL), copper (I)iodide (73.7 mg) and THF (5 mL) was stirred under microwave irradiationat 90° C. for 2 hours. The mixture was diluted with water, and extractedwith ethyl acetate. The organic layer was washed with a saturated brine,then dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (99 mg).

¹H NMR (300 MHz, DMSO-d₆) δ3.74 (3H, s), 5.61 (2H, s), 6.86 (1H, d,J=3.3 Hz), 7.04-7.12 (1H, m), 7.14-7.26 (2H, m), 7.37-7.50 (1H, m), 8.00(1H, d, J=3.3 Hz), 8.50 (1H, d, J=2.4 Hz), 8.53 (1H, s), 8.68 (1H, d,J=2.4 Hz).

d)1-(3-fluorobenzyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

Sodium methoxide (28% in methanol solution) (90 mg) was added to2-chloro-1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine(90 mg) in THF (5 mL) at room temperature. The mixture was stirred atroom temperature for 30 minutes. The reaction mixture was diluted with asaturated aqueous ammonium chloride solution at room temperature, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate), and crystallized fromethanol/water to obtain the title compound (56.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.72 (3H, s), 4.24 (3H, s), 5.30 (2H, s),6.81 (1H, d, J=3.2 Hz), 7.08-7.23 (3H, m), 7.36-7.48 (1H, m), 7.92 (1H,d, J=3.2 Hz), 8.16 (1H, d, J=2.4 Hz), 8.39 (1H, d, J=2.4 Hz), 8.50 (1H,s).

Example 441-(3-(difluoromethoxy)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(3-(difluoromethoxy)benzyl)-5-iodopyridine-2,3-diamine

A mixture of 3-(difluoromethoxy)benzaldehyde (429 mg),5-iodopyridine-2,3-diamine (451 mg), THF (8 mL) and acetic acid (0.277mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.Sodium borohydride (181 mg) was added to a solution of the residue inmethanol (8 mL) at room temperature. The mixture was stirred overnightat room temperature. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (660mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.30 (2H, d, J=5.8 Hz), 5.66 (1H, t, J=5.9Hz), 5.78 (2H, s), 6.66 (1H, d, J=1.9 Hz), 6.95-7.48 (2H, m), 7.06 (1H,dd, J=8.0, 2.2 Hz), 7.16 (1H, s), 7.37-7.44 (2H, m).

b)1-(3-(difluoromethoxy)benzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture ofN3-(3-(difluoromethoxy)benzyl)-5-iodopyridine-2,3-diamine (0.66 g) andtrimethyl orthoacetate (5 mL) at room temperature. The mixture wasstirred at 60° C. for 3 hours. The reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (0.492 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.53 (2H, s), 6.92 (1H, d,J=7.6 Hz), 6.96-7.49 (1H, m), 7.01 (1H, s), 7.11 (1H, dd, J=8.3, 2.2Hz), 7.35-7.44 (1H, m), 8.39 (1H, d, J=1.9 Hz), 8.52 (1H, d, J=1.9 Hz).

c)1-(3-(difluoromethoxy)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

1-(3-(difluoromethoxy)benzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine(157.9 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (59.6 mg), potassiumphosphate (242 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (64.9mg), copper (I) iodide (43.5 mg) and THF (2 mL) was stirred undermicrowave irradiation at 150° C. for 2.5 hours. The mixture was cooledto room temperature, then poured into a saturated aqueous ammoniumchloride solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, then dried over magnesium sulfate,and concentrated under reduced pressure. The residue was fractionated byNH silica gel column chromatography (methanol/ethyl acetate) and HPLC(C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)) toobtain the title compound (93 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.62 (3H, s), 3.70 (3H, s), 5.57 (2H, s),6.83 (1H, d, J=3.2 Hz), 6.91-7.50 (5H, m), 7.96 (1H, d, J=3.2 Hz), 8.29(1H, d, J=2.4 Hz), 8.51 (1H, s), 8.54 (1H, d, J=2.4 Hz).

Example 481-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-aminea) 1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one

Under a dry atmosphere, a mixture ofN3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (2.2 g), CDI (1.976g) and THF (150 mL) was stirred at 60° C. for 16 hours. The mixture wasquenched with water at room temperature, and diluted with ethyl acetate.The organic layer was sequentially washed with a saturated aqueousammonium chloride solution, water and a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas washed with ethyl acetate to obtain the title compound (2 g).

¹H NMR (300 MHz, DMSO-d₆) δ5.02 (2H, s), 6.99-7.25 (3H, m), 7.84 (1H, d,J=1.8 Hz), 8.13 (1H, d, J=1.8 Hz), 11.88 (1H, brs).

b) 2-chloro-1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine

A mixture of1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one (2 g)and phosphorus oxychloride (24.13 mL) was stirred under a nitrogenatmosphere at 100° C. for 17 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with THF,neutralized with a saturated aqueous sodium hydrogen carbonate solutionat 0° C., and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was washed with IPE to obtain the titlecompound (1.97 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.58 (2H, s), 6.98 (3H, d, J=6.0 Hz), 8.62(2H, dd, J=11.5, 1.9 Hz).

c)2-chloro-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-chloro-1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine (980mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (469 mg), potassium phosphate(1539 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.381 mL), copper(I) iodide (230 mg) and THF (5 mL) was stirred under microwaveirradiation at 90° C. for 3 hours. The mixture was diluted with waterand an aqueous ammonia solution at room temperature, and extracted withethyl acetate. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (440 mg).

¹H NMR (300 MHz, DMSO-d₆) δ3.77 (3H, s), 5.61 (2H, s), 6.87 (1H, d,J=3.2 Hz), 7.04-7.26 (3H, m), 8.00 (1H, d, J=3.2 Hz), 8.47-8.59 (2H, m),8.64-8.78 (1H, m).

d)1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-amine

A mixture of2-chloro-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine(120 mg), ammonia (2 M in IPA solution) (15 mL) and THF (5 mL) wasstirred under microwave irradiation at 100° C. for 5 hours. The mixturewas diluted with water at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (41 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.70 (3H, s), 5.32 (2H, s), 6.76 (1H, d,J=3.2 Hz), 6.91-7.00 (2H, m), 7.14-7.24 (1H, m), 7.30 (2H, s), 7.78 (1H,d, J=2.4 Hz), 7.85 (1H, d, J=3.2 Hz), 8.14 (1H, d, J=2.4 Hz), 8.47 (1H,s).

Example 681-(3-fluoro-5-(trifluoromethyl)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-iodopyridine-2,3-diamine

A mixture of 3-fluoro-5-(trifluoromethyl)benzaldehyde (0.72 mL),5-iodopyridine-2,3-diamine (1.01 g), THF (10 mL) and acetic acid (0.62mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.Sodium borohydride (0.406 g) was added to a solution of the residue inmethanol (5 mL) at room temperature. The mixture was stirred overnightat room temperature. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (1.51g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.41 (2H, d, J=5.8 Hz), 5.71 (1H, t, J=5.7Hz), 5.80 (2H, s), 6.71 (1H, d, J=1.7 Hz), 7.43 (1H, d, J=1.9 Hz),7.50-7.64 (3H, m).

b)1-(3-fluoro-5-(trifluoromethyl)benzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture ofN3-(3-fluoro-5-(trifuoromethyl)benzyl)-5-iodopyridine-2,3-diamine (1.51g) and trimethyl orthoacetate (5 mL) at room temperature. Under a dryatmosphere, the mixture was stirred at 60° C. for 3 hours. The reactionmixture was poured into a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (1.03g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (3H, s), 5.63 (2H, s), 7.19-7.26 (1H,m), 7.45 (1H, s), 7.62-7.70 (1H, m), 8.41 (1H, d, J=2.0 Hz), 8.53 (1H,d, J=1.9 Hz).

c)1-(3-fluoro-5-(trifluoromethyl)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluoro-5-(trifuoromethyl)benzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine(139 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (50 mg), potassiumphosphate (203 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.06mL), copper (I) iodide (36.5 mg) and THF (2 mL) was stirred undermicrowave irradiation at 100° C. for 2 hours. The mixture was cooled toroom temperature, then diluted with a saturated aqueous ammoniumchloride solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, then dried over magnesium sulfate,and concentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) to obtain thetitle compound (113 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 3.68 (3H, s), 5.67 (2H, s),6.83 (1H, d, J=3.3 Hz), 7.26 (1H, d, J=9.3 Hz), 7.50 (1H, s), 7.68 (1H,d, J=8.7 Hz), 7.96 (1H, d, J=3.2 Hz), 8.29 (1H, d, J=2.4 Hz), 8.51 (1H,s), 8.56 (1H, d, J=2.4 Hz).

Example 791-(3-chloro-5-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-(3-chloro-5-fluorobenzyl)-5-iodopyridine-2,3-diamine

A mixture of 3-chloro-5-fluorobenzaldehyde (0.623 g),5-iodopyridine-2,3-diamine (0.77 g), THF (10 mL) and acetic acid (0.472mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated. Toa solution of the residue in methanol (5 mL) was added sodiumborohydride (0.31 g) at room temperature. The mixture was stirredovernight at room temperature. The reaction mixture was poured intowater, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.32 (2H, d, J=5.8 Hz), 5.69 (1H, t, J=5.9Hz), 5.79 (2H, s), 6.67 (1H, d, J=1.8 Hz), 7.16-7.23 (1H, m), 7.27-7.35(2H, m), 7.43 (1H, d, J=1.9 Hz).

b) 1-(3-chloro-5-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

Concentrated hydrochloric acid (500 μL) was added to a mixture ofN3-(3-chloro-5-fluorobenzyl)-5-iodopyridine-2,3-diamine (1 g) andtrimethyl orthoacetate (5 mL) at room temperature. The mixture wasstirred at 60° C. for 3 hours. The reaction mixture was poured into asaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The organic layer was washed with a saturated brine,dried over magnesium sulfate, and then concentrated. The residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (0.77 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.54 (2H, s), 6.92-7.00 (1H,m), 7.06 (1H, s), 7.40 (1H, dt, J=8.7, 2.2 Hz), 8.40 (1H, d, J=1.9 Hz),8.53 (1H, d, J=1.9 Hz).

c)1-(3-chloro-5-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-chloro-5-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine(110.7 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (43.2 mg), potassiumphosphate (176 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.052mL), copper (I) iodide (31.5 mg) and THF (2 mL) was stirred undermicrowave irradiation at 100° C. for 2 hours. The mixture was cooled toroom temperature, then poured into a saturated aqueous ammonium chloridesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) andcrystallized from ethanol/IPE to obtain the title compound (54.7 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.72 (3H, s), 5.57 (2H, s),6.83 (1H, d, J=3.2 Hz), 6.98-7.05 (1H, m), 7.10-7.14 (1H, m), 7.42 (1H,dt, J=8.7, 2.1 Hz), 7.97 (1H, d, J=3.2 Hz), 8.28 (1H, d, J=2.4 Hz), 8.51(1H, s), 8.55 (1H, d, J=2.4 Hz).

Example 82(1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanola) (1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol

A mixture of N3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (9 g),glycolic acid (48 g) and THF (9 mL) was stirred under microwaveirradiation at 150° C. for 1.5 hours. The mixture was neutralized with asaturated aqueous sodium hydrogen carbonate solution at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexame and methanol/ethyl acetate) toobtain the title compound (4.9 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.77 (2H, s), 5.61 (2H, s), 5.79-6.07 (1H,m), 6.81-7.08 (2H, m), 7.12-7.30 (1H, m), 8.33 (1H, d, J=1.9 Hz), 8.57(1H, d, J=2.0 Hz).

b) 2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine

1H-imidazole (105 mg) and tert-butylchlorodiphenylsilane (0.39 mL) wereadded to a solution of(1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol(200 mg) in DMF (1.5 mL). The mixture was stirred at room temperaturefor 10 minutes. The reaction mixture was quenched with a saturatedaqueous sodium hydrogen carbonate solution at 0° C., and extracted withethyl acetate. The organic layer was washed with water and a saturatedbrine, dried over magnesium sulfate, and then concentrated. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (256 mg).

¹H NMR (300 MHz, DMSO-d₆) δ0.90 (9H, s), 4.81-5.11 (2H, m), 5.54-5.83(2H, m), 6.74-6.91 (2H, m), 7.12-7.23 (1H, m), 7.37-7.53 (6H, m),7.57-7.65 (4H, m), 8.19-8.47 (1H, m), 8.55-8.71 (1H, m).

c)2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridine(4.92 g), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (1.2 g), potassiumphosphate (4.9 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (2.76 mL),copper (I) iodide (1.46 g) and THF (72 mL) was stirred under microwaveirradiation at 100° C. for 1.5 hours. The mixture was diluted with asaturated aqueous sodium hydrogen carbonate solution and an aqueousammonia solution at room temperature, and extracted with ethyl acetate.The organic layer was concentrated under reduced pressure. The residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (3.23 g).

MS: [M+H]⁺ 661.2

d)(1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol

TBAF (1M in THF solution) (0.239 mL) was added to a solution of2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine(105 mg) in THF (2 mL) at room temperature. The mixture was stirred atroom temperature for 30 minutes. The residue was purified by NH silicagel column chromatography (methanol/ethyl acetate) to obtain the titlecompound (44.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ3.67 (3H, s), 4.66-4.96 (2H, m), 5.46-5.74(2H, m), 5.82-6.09 (1H, m), 6.64-6.89 (1H, m), 6.93-7.09 (2H, m),7.13-7.33 (1H, m), 7.96 (1H, d, J=3.3 Hz), 8.16-8.32 (1H, m), 8.51 (2H,s).

Example 961-((6-fluoropyridin-2-yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) N3-((6-fluoropyridin-2-yl)methyl)-5-iodopyridine-2,3-diamine

A mixture of 6-fluoropicolinaldehyde (2.97 g),5-iodopyridine-2,3-diamine (5.08 g), THF (50 mL) and acetic acid (3.12mL) was stirred overnight at room temperature. The reaction mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated. Toa solution of the residue in methanol (5 mL) was added sodiumborohydride (2.044 g) at room temperature. The mixture was stirredovernight at room temperature. The reaction mixture was poured intowater, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (5.72 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.34 (2H, d, J=5.9 Hz), 5.77-5.89 (3H, m),6.63 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=8.1, 2.4 Hz), 7.30 (1H, dd,J=7.4, 2.4 Hz), 7.41 (1H, d, J=1.9 Hz), 7.89-8.04 (1H, m).

b)1-((6-fluoropyridin-2-yl)methyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture ofN3-((6-fluoropyridin-2-yl)methyl)-5-iodopyridine-2,3-diamine (1.09 g),acetic acid (0.218 mL), DMAP (0.019 g), propylphosphonic anhydride (50%in ethyl acetate solution) (2.79 mL), DIPEA (1.106 mL) and THF (12 mL)was stirred under microwave irradiation at 180° C. for 2 hours. Thereaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (0.71g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H, s), 5.59 (2H, s), 7.12 (1H, dd,J=8.2, 2.5 Hz), 7.28 (1H, dd, J=7.3, 2.4 Hz), 8.01 (1H, q, J=8.2 Hz),8.40 (1H, d, J=1.9 Hz), 8.50 (1H, d, J=1.9 Hz).

c)1-((6-fluoropyridin-2-yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-((6-fluoropyridin-2-yl)methyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine(149.5 mg), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (63.6 mg), potassiumphosphate (259 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.128mL), copper (1) iodide (77 mg) and THF (1 mL) was stirred undermicrowave irradiation at 120° C. for 2 hours. The mixture was pouredinto a saturated aqueous ammonium chloride solution, and extracted withethyl acetate. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound (75mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 3.70 (3H, s), 5.62 (2H, s),6.83 (1H, d, J=3.2 Hz), 7.13 (1H, dd, J=8.0, 2.4 Hz), 7.31 (1H, dd,J=7.2, 2.4 Hz), 7.95 (1H, d, J=3.2 Hz), 7.98-8.08 (1H, m), 8.26 (1H, d,J=2.4 Hz), 8.50 (1H, s), 8.53 (1H, d, J=2.4 Hz).

Example 981-((6-fluoropyridin-2-yl)methyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridinea) 1-((6-fluoropyridin-2-yl)methyl)-6-1H-imidazo[4,5-b]pyridin-2(3H)-one

Under a nitrogen atmosphere, a mixture ofN3-((6-fluoropyridin-2-yl)methyl)-5-iodopyridine-2,3-diamine (4.62 g),CDI (4.35 g) and THF (50 mL) was stirred overnight at 60° C. The mixturewas diluted with THF, sequentially washed with a saturated aqueousammonium chloride solution and a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas washed with ethyl acetate to obtain the title compound (3.89 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.09 (2H, s), 7.09 (1H, dd, J=8.1, 2.3 Hz),7.25 (1H, dd, J=7.4, 2.3 Hz), 7.78 (1H, d, J=1.7 Hz), 7.92-8.03 (1H, m),8.13 (1H, d, J=1.8 Hz), 11.86 (1H, s).

b)2-chloro-1-((6-fluoropyridin-2-yl)methyl)-6-iodo-1H-imidazo[4,5-b]pyridine

A mixture of1-((6-fluoropyridin-2-yl)methyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one(3.88 g) and phosphorus oxychloride (50 mL) was stirred under a nitrogenatmosphere at 100° C. for 21 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was neutralized with asaturated aqueous sodium hydrogen carbonate solution at 0° C., andextracted with ethyl acetate/THF. The organic layer was washed with asaturated brine, dried over magnesium sulfate, and then concentrated.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane), and washed with ethyl acetate to obtain the titlecompound (1.36 g).

MS: [M+H]⁺ 388.9

c)2-chloro-1-((6-fluoropyridin-2-yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

A mixture of2-chloro-1-((6-fluoropyridin-2-yl)methyl)-6-iodo-1H-imidazo[4,5-b]pyridine(1.18 g), 4-methoxy-5H-pyrrolo[3,2-d]pyrimidine (0.589 g), potassiumphosphate (1.934 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.864g), copper (I) iodide (0.578 g) and THF (15 mL) was stirred undermicrowave irradiation at 95° C. for 90 minutes. The mixture was dilutedwith water at room temperature, and extracted with ethyl acetate. Theorganic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (methanol/ethylacetate) to obtain the title compound (770 mg).

MS: [M+H]⁺ 410.2

d)1-((6-fluoropyridin-2-yl)methyl)-2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

Sodium methoxide (28% in methanol solution) (0.2 mL) was added to2-chloro-1-((6-fluoropyridin-2-yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine(380 mg) in THF (5 mL) at room temperature. Under a dry atmosphere, themixture was stirred at room temperature for 30 minutes. The reactionmixture was diluted with water at room temperature, and extracted withethyl acetate. The organic layer was washed with water and a saturatedbrine, dried over magnesium sulfate, and then concentrated. The residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) and HPLC (C18, mobile phase: water/acetonitrile (0.1%TFA-containing system)), and washed with ethyl acetate/IPE to obtain thetitle compound (56.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.73 (3H, s), 4.19 (3H, s), 5.39 (2H, s),6.80 (1H, d, J=3.2 Hz), 7.12 (1H, dd, J=8.1, 2.4 Hz), 7.25 (1H, dd,J=7.4, 2.2 Hz), 7.91 (1H, d, J=3.1 Hz), 7.96-8.09 (2H, m), 8.40 (1H, d,J=2.4 Hz), 8.49 (1H, s).

Example 1021-(3-fluorobenzyl)-6-(7-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) 7-methoxy-1H-pyrrolo[3,2-b]pyridine

A mixture of 7-chloro-1H-pyrrolo[3,2-b]pyridine (1 g), methanol (20 mL)and sodium methoxide (28% in methanol solution) (1.817 mL) was stirredunder microwave irradiation at 150° C. for 10 hours. The reactionmixture was poured into a saturated aqueous ammonium chloride solutionat room temperature, and extracted with ethyl acetate. The organic layerwas dried over magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) and NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (0.113 g).

¹H NMR (300 MHz, DMSO-d₆) δ3.97 (3H, s), 6.48 (1H, dd, J=3.1, 2.1 Hz),6.73 (1H, d, J=5.4 Hz), 7.42-7.49 (1H, m), 8.18 (1H, d, J=5.4 Hz), 11.45(1H, brs).

b)1-(3-fluorobenzyl)-6-(7-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (400 mg),7-methoxy-1H-pyrrolo[3,2-b]pyridine (194 mg), potassium phosphate (730mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (190 mg), copper (I)iodide (125 mg) and THF (3 mL) was stirred under microwave irradiationat 130° C. for 3 hours. The mixture was poured into water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) and silica gelcolumn chromatography (methanol/ethyl acetate) to obtain the titlecompound (154 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 3.55 (3H, s), 5.56 (2H, s),6.76 (1H, d, J=3.3 Hz), 6.80 (1H, d, J=5.5 Hz), 6.98 (1H, d, J=7.7 Hz),7.02-7.10 (1H, m), 7.11-7.21 (1H, m), 7.36-7.48 (1H, m), 7.72 (1H, d,J=3.3 Hz), 8.16 (1H, d, J=2.4 Hz), 8.29 (1H, d, J=5.5 Hz), 8.48 (1H, d,J=2.4 Hz).

Example 1051-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-7-methoxy-1H-pyrazolo[4,3-b]pyridinea) 7-methoxy-1H-pyrazolo[4,3-b]pyridine

A mixture of 7-chloro-1H-pyrazolo[4,3-b]pyridine (300 mg), methanol (5mL) and sodium methoxide (555 mg) was stirred under microwaveirradiation at 100° C. for 3 hours and at 150° C. for 8 hours. Thereaction mixture was poured into a saturated aqueous ammonium chloridesolution at room temperature, and extracted with ethyl acetate. Theorganic layer was dried over magnesium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate), and crystallized from ethylacetate/hexane to obtain the title compound (93 mg).

¹H NMR (300 MHz, DMSO-d₆) δ4.03 (3H, s), 6.91 (1H, d, J=5.1 Hz), 8.19(1H, s), 8.36 (1H, d, J=5.1 Hz), 13.55 (1H, brs).

b)1-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-7-methoxy-1H-pyrazolo[4,3-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (224 mg),7-methoxy-1H-pyrrolo[4,3-b]pyridine (100 mg), potassium phosphate (409mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (106 mg), copper (I)iodide (69.7 mg) and THF (3 mL) was stirred under microwave irradiationat 150° C. for 4 hours. The mixture was poured into water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) and silica gelcolumn chromatography (methanol/ethyl acetate), and crystallized fromethyl acetate/heptane to obtain the title compound (41.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.63 (3H, s), 3.69 (3H, s), 5.59 (2H, s),6.97 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=5.2 Hz), 7.05-7.11 (1H, m),7.12-7.21 (1H, m), 7.37-7.48 (1H, m), 8.25 (1H, d, J=2.4 Hz), 8.48 (1H,d, J=5.2 Hz), 8.53 (1H, s), 8.59 (1H, d, J=2.4 Hz).

Example 1101-(3-fluorobenzyl)-6-(3-methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) 3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

Sodium hydride (60%, oil) (0.846 g) was added to a mixture of3-chloro-5H-pyrrolo[2,3-b]pyrazine (2.5 g) and DMF (25 mL) at 0° C. Themixture was stirred for 5 minutes, and 2-(trimethylsilyl)ethoxymethylchloride (3.75 mL) was then added to the mixture at 0° C. The mixturewas stirred under an argon atmosphere at room temperature for 2 hours.The reaction mixture was poured into a saturated aqueous ammoniumchloride solution at 0° C., and extracted with ethyl acetate. Theorganic layer was washed with water and a saturated brine, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (4.42 g).

¹H NMR (300 MHz, DMSO-d₆) δ −0.14-−0.07 (9H, m), 0.76-0.88 (2H, m), 3.52(2H, dd, J=8.5, 7.6 Hz), 5.60 (2H, s), 6.81 (1H, d, J=3.7 Hz), 8.10 (1H,d, J=3.8 Hz), 8.56 (1H, s).

b)3-methoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine

A mixture of 3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (1 g),N-methyl-2-pyrrolidone (10 mL) and sodium methoxide (28% methanolsolution) (0.68 g) was stirred at 70° C. for 2 hours. The reactionmixture was poured into water, and extracted with ethyl acetate. Theorganic layer was washed with water and a saturated brine, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (0.693 g).

¹H NMR (300 MHz, DMSO-d₆) δ −0.17-−0.07 (9H, m), 0.76-0.90 (2H, m),3.46-3.61 (2H, m), 3.96 (3H, s), 5.56 (2H, s), 6.64 (1H, d, J=3.8 Hz),7.70 (1H, d, J=3.7 Hz), 8.13 (1H, s).

c) 3-methoxy-5H-pyrrolo[2,3-b]pyrazine

TFA (3 mL) was added to3-methoxy-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(1.02 g) at room temperature. Under a dry atmosphere, the mixture wasstirred at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure. To the residue were added ethanoland ammonia (28% in aqueous solution) at 0° C. Under a dry atmosphere,the mixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated under reduced pressure. The residue was washedwith water and IPE, and dried under reduced pressure to obtain the titlecompound (0.461 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.92 (3H, s), 6.54 (1H, dd, J=3.5, 0.9 Hz),7.49-7.54 (1H, m), 8.06 (1H, s), 11.79 (1H, brs).

d)1-(3-fluorobenzyl)-6-(3-methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of1-(3-fluorobenzyl)-6-iodo-2-methyl-1H-imidazo[4,5-b]pyridine (222 mg),3-methoxy-5H-pyrrolo[2,3-b]pyrazine (90 mg), potassium phosphate (384mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.104 mL), copper (I)iodide (63.2 mg) and THF (5 mL) was stirred under microwave irradiationat 100° C. for 3 hours. The mixture was diluted with water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (methanol/ethyl acetate), and pulverized withethyl acetate to obtain the title compound (71.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 3.74 (3H, s), 5.62 (2H, s),6.87 (1H, d, J=3.8 Hz), 6.94-7.20 (3H, m), 7.33-7.45 (1H, m), 8.07 (1H,d, J=3.8 Hz), 8.19 (1H, s), 8.54 (1H, d, J=2.4 Hz), 8.81 (1H, d, J=2.4Hz).

Example 1341-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanola)1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanone

A mixture ofchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.31 g), cesium fluoride (4.33 g),3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine(3.68 g), tributyl(1-ethoxyvinyl)stannane (5.8 mL) and DME (40 mL) wasstirred under an argon atmosphere at 80° C. for 3 hours. The mixture waspoured into an aqueous potassium fluoride solution, insolubles wereremoved, and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous potassium fluoride solution and asaturated brine, then dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane). The obtained residue (3.86 g) wasdiluted with methanol (100 mL)/hydrochloric acid (2 N in aqueoussolution) (25 mL) at room temperature. The mixture was stirred at roomtemperature for 30 minutes. The mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, then dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (3.05g).

¹H NMR (300 MHz, DMSO-d₆) δ −0.16-−0.09 (9H, m), 0.80-0.91 (2H, m), 2.71(3H, s), 3.53-3.64 (2H, m), 5.72 (2H, s), 6.88 (1H, d, J=3.7 Hz), 8.38(1H, d, J=3.7 Hz), 9.05 (1H, s).

b) 1-(5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol mono-TFA salt

Sodium borohydride (0.398 g) was added to a mixture of1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanone(3.05 g) and methanol (60 mL) at 0° C. The mixture was stirred at roomtemperature for 15 minutes. The mixture was poured into hydrochloricacid (0.1 N in aqueous solution), and extracted with ethyl acetate. Theorganic layer was washed with water and a saturated brine, then driedover sodium sulfate, and concentrated under reduced pressure. A mixtureof the residue and TFA (20 mL) was stirred at room temperature for 1hour, and concentrated under reduced pressure. The residue was dilutedwith ethanol/ammonia (28% in aqueous solution). The mixture was stirredat 60° C. for 15 minutes, and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (2.22 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.45 (3H, d, J=6.5 Hz), 4.87 (1H, q, J=6.5Hz), 5.37 (1H, brs), 6.58 (1H, dd, J=3.6, 1.8 Hz), 6.86-7.34 (1H, m),7.79 (1H, dd, J=3.5, 2.8 Hz), 8.53 (1H, s), 11.89 (1H, brs).

c)1-(5-(1-(3,5-difluorobenzyl)-2-(isopropylthio)-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol

A mixture of1-(3,5-difluorobenzyl)-6-iodo-2-(isopropylthio)-1H-imidazo[4,5-b]pyridine(707 mg), a 1-(5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol mono-TFA salt (400mg), potassium phosphate (919 mg),trans-N,N′-dimethylcyclohexane-1,2-diamine (0.249 mL), copper (I) iodide(151 mg) and THF (8 mL) was stirred under microwave irradiation at 100°C. for 3 hours. The mixture was diluted with water at room temperature,and extracted with ethyl acetate. The organic layer was washed with anaqueous ammonium chloride solution and a saturated brine, then driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (methanol/ethylacetate) to obtain the title compound (610 mg).

¹H NMR (300 MHz, DMSO-d₆) δ1.39 (3H, d, J=6.5 Hz), 1.49 (6H, d, J=6.8Hz), 4.11-4.25 (1H, m), 4.84 (1H, dd, J=6.5, 4.8 Hz), 5.44-5.60 (3H, m),6.89-7.02 (3H, m), 7.17-7.29 (1H, m), 8.33 (1H, d, J=3.9 Hz), 8.52 (1H,d, J=2.4 Hz), 8.69 (1H, s), 8.85 (1H, d, J=2.4 Hz).

d)1-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol

Methachloroperbenzoic acid (0.73 g) was added to a mixture of1-(5-(1-(3,5-difluorobenzyl)-2-(isopropylthio)-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(1.18 g) and acetonitrile (30 mL) at 0° C. The mixture was stirred at 0°C. for 2 hours, and sodium methoxide (28% in methanol solution) (1.5 mL)was added at 0° C. The mixture was stirred at room temperature for 15minutes. The reaction mixture was poured into water at room temperature,and extracted with ethyl acetate. The organic layer was washed withwater and a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(0.53 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.39 (3H, d, J=6.5 Hz), 4.24 (3H, s),4.77-4.89 (1H, m), 5.35 (2H, s), 5.50 (1H, d, J=4.8 Hz), 6.91 (1H, d,J=3.8 Hz), 7.02-7.12 (2H, m), 7.16-7.27 (1H, m), 8.29 (1H, d, J=3.8 Hz),8.36 (1H, d, J=2.4 Hz), 8.64-8.71 (2H, m).

Example 158(R)-1-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(Optical Isomer)

A racemate of1-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(553.5 mg) was fractionated by SFC (column: CHIRALPAK ASH (LA005), 20 mmID×250 mm L, manufactured by Daicel Chemical Industries Ltd, mobilephase: CO₂/ethanol (containing 0.3% diethylamine)=700/300), andcrystallized from ethanol/water to obtain the title compound (0.219 g)with a smaller retention time.

¹H NMR (300 MHz, DMSO-d₆) δ1.39 (3H, d, J=6.5 Hz), 4.24 (3H, s),4.75-4.93 (1H, m), 5.35 (2H, s), 5.50 (1H, d, J=4.8 Hz), 6.91 (1H, d,J=3.8 Hz), 7.01-7.11 (2H, m), 7.16-7.27 (1H, m), 8.29 (1H, d, J=3.8 Hz),8.36 (1H, d, J=2.4 Hz), 8.64-8.70 (2H, m).

Example 159(S)-1-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(Optical Isomer)

A racemate of1-(5-(1-(3,5-difluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(553.5 mg) was fractionated by SFC (column: CHIRALPAK ASH (LA005), 20 mmID×250 mm L, manufactured by Daicel Chemical Industries Ltd, mobilephase: CO₂/ethanol (containing 0.3% diethylamine)=700/300), andcrystallized from ethanol/water to obtain the title compound (0.197 g)with a larger retention time.

¹H NMR (300 MHz, DMSO-d₆) δ1.39 (3H, d, J=6.5 Hz), 4.24 (3H, s),4.78-4.90 (1H, m), 5.35 (2H, s), 5.50 (1H, d, J=4.7 Hz), 6.91 (1H, d,J=3.9 Hz), 7.01-7.11 (2H, m), 7.16-7.27 (1H, m), 8.29 (1H, d, J=3.9 Hz),8.36 (1H, d, J=2.4 Hz), 8.66-8.69 (2H, m).

Example 1601-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(Optical Isomer) a)1-(3-fluorobenzyl)-6-iodo-2-(isopropylthio)-1H-imidazo[4,5-b]pyridine

Under a dry atmosphere, a mixture ofN3-(3-fluorobenzyl)-5-iodopyridine-2,3-diamine (5 g), CDI (4.75 g) andTHF (50 mL) was stirred at 60° C. for 16 hours. The reaction mixture wasquenched with water at room temperature, and extracted with ethylacetate. The organic layer was sequentially washed with a saturatedaqueous ammonium chloride solution, water and a saturated brine, thendried over sodium sulfate, and concentrated under reduced pressure toobtain a brown solid as1-(3-fluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2(3H)-one. A mixtureof the obtained solid and phosphorus oxychloride (50 mL) was stirred at100° C. for 2 days. The reaction mixture was concentrated under reducedpressure. The residue was diluted with THF, poured into a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with water and a saturated brine,dried over sodium sulfate, and then concentrated. The residue wasdiluted with THF (100 mL). To the mixture was added sodium2-propanethiolate (2.066 g) at 0° C. Under a nitrogen atmosphere, themixture was stirred overnight at room temperature. The reaction mixturewas diluted with ethyl acetate. Insolubles were removed, and the mixturewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (5.87 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.45 (6H, d, J=6.8 Hz), 4.05-4.16 (1H, m),5.42 (2H, s), 6.93 (1H, d, J=7.7 Hz), 7.00-7.19 (2H, m), 7.34-7.44 (1H,m), 8.41 (1H, d, J=1.9 Hz), 8.51 (1H, d, J=1.9 Hz).

b)1-(5-(1-(3-fluorobenzyl)-2-(isopropylthio)-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol

A mixture of1-(3-fluorobenzyl)-6-iodo-2-(isopropylthio)-1H-imidazo[4,5-b]pyridine(1017 mg), a 1-(5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol mono-TFA salt (600mg), potassium phosphate (1378 mg),trans-N,N′-dimethylcyclohexane-1,2-diamine (0.374 mL), copper (I) iodide(227 mg) and THF (10 mL) was stirred under microwave irradiation at 100°C. for 3 hours. The mixture was diluted with water at room temperature,and extracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(600 mg).

¹H NMR (300 MHz, DMSO-d₆) δ1.40 (3H, d, J=6.4 Hz), 1.49 (6H, d, J=6.8Hz), 4.10-4.26 (1H, m), 4.72-4.91 (1H, m), 5.41-5.56 (3H, m), 6.93 (1H,d, J=3.8 Hz), 7.02-7.24 (3H, m), 7.35-7.48 (1H, m), 8.33 (1H, d, J=3.8Hz), 8.53 (1H, d, J=2.4 Hz), 8.68 (1H, s), 8.83 (1H, d, J=2.3 Hz).

c)1-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(Optical Isomer)

Methachloroperbenzoic acid (0.79 g) was added to a mixture of1-(5-(1-(3-fluorobenzyl)-2-(isopropylthio)-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(1.24 g), DMF (5 mL) and ethyl acetate (30 mL) at 0° C. The mixture wasstirred at room temperature for 3 hours, and then concentrated underreduced pressure. The residue was diluted with THF (20 mL), and sodiummethoxide (28% in methanol solution) (2.8 mL) was added at 0° C. Themixture was stirred at room temperature for 10 minutes. The reactionmixture was poured into water at room temperature, and extracted withethyl acetate. The organic layer was washed with water and a saturatedbrine, dried over sodium sulfate, and then concentrated. The residue waspurified by silica gel column chromatography (methanol/ethyl acetate) toobtain1-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol.A racemate of1-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(688 mg) was fractionated by SFC (column: CHIRALPAK ASH(S90ASHSCZ-RA001), 30 mm ID×250 mm L, manufactured by Daicel ChemicalIndustries Ltd, mobile phase: CO₂/ethanol=800/200), and a compound witha smaller retention time was crystallized from ethanol/water to obtainthe title compound (335 mg).

¹H NMR (300 MHz, DMSO-d₆) δ1.40 (3H, d, J=6.5 Hz), 4.24 (3H, s), 4.84(1H, dd, J=6.5, 4.8 Hz), 5.34 (2H, s), 5.50 (1H, d, J=4.8 Hz), 6.91 (1H,d, J=3.8 Hz), 7.10-7.25 (3H, m), 7.36-7.46 (1H, m), 8.28 (1H, d, J=3.8Hz), 8.37 (1H, d, J=2.4 Hz), 8.64-8.70 (2H, m).

Example 1611-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(Optical Isomer)

A racemate of1-(5-(1-(3-fluorobenzyl)-2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol(688 mg) was fractionated by SFC (column: CHIRALPAK ASH(S90ASHSCZ-RA001), 30 mm ID×250 mm L, manufactured by Daicel ChemicalIndustries Ltd, mobile phase: CO₂/ethanol=800/200), and a compound witha larger retention time was crystallized from ethanol/water to obtainthe title compound (309 mg).

¹H NMR (300 MHz, DMSO-d₆) δ1.40 (3H, d, J=6.4 Hz), 4.24 (3H, s),4.79-4.90 (1H, m), 5.34 (2H, s), 5.50 (1H, d, J=4.7 Hz), 6.91 (1H, d,J=3.8 Hz), 7.08-7.25 (3H, m), 7.40 (1H, d, J=6.0 Hz), 8.28 (1H, d, J=4.0Hz), 8.37 (1H, d, J=2.4 Hz), 8.64-8.70 (2H, m).

Example 1621-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[1,2-b]pyridin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine

A solution of 5-bromopyridine-2,3-diamine (83.5 g) in acetic acid (500mL) was heated and refluxed for 2 days. The reaction mixture wasconcentrated under reduced pressure. The residue was pulverized withIPE, and dried under reduced pressure to obtain the title compound (93g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.51-2.53 (3H, m), 8.12 (1H, d, J=2.2 Hz),8.31 (1H, d, J=2.2 Hz), 12.96 (1H, brs).

b) 6-bromo-1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine

Potassium hydroxide (2.381 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3 g),1-(bromomethyl)-3,5-difluorobenzene (2.014 mL) and THF (40 mL) at 60° C.The reaction mixture was stirred overnight at 60° C. The reactionmixture was cooled to room temperature, then poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane), and crystallized fromethanol/IPE. The obtained precipitate was collected by filtration, andwashed with IPE to obtain the title compound (2.000 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (3H, s), 5.55 (2H, s), 6.82-6.93 (2H,m), 7.20 (1H, tt, J=9.4, 2.2 Hz), 8.31 (1H, d, J=2.2 Hz), 8.43 (1H, d,J=2.2 Hz).

c)1-(3,5-difluorobenzyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine (400mg), bis (pinacolato)diboron (468 mg), a[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloridedichloromethane complex (108 mg), potassium acetate (452 mg), THF (9 mL)and DMSO (0.9 mL) was stirred under microwave irradiation at 110° C. for1 hour. The reaction mixture was diluted with ethyl acetate, andinsolubles were removed by filtration through Celite. The filtrate waspoured into water, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, then dried over magnesium sulfate,and concentrated under reduced pressure. The residue was collected byfiltration, and washed with IPE to obtain the title compound (387 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (12H, s), 2.57 (3H, s), 5.65 (2H, s),6.71-6.85 (2H, m), 7.19 (1H, tt, J=9.3, 2.2 Hz), 8.10 (1H, d, J=1.5 Hz),8.60 (1H, d, J=1.5 Hz).

d) Ethyl 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate

A mixture of 1H-pyrrol-1-amine (9.62 mL) and diethyl(ethoxymethylene)malonate (30 mL) was stirred at 125° C. for 2 hours.The reaction mixture was diluted with diphenyl ether (40 mL), and theresulting mixture was stirred at 200° C. for 3 hours. The reactionmixture was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (15.97 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (3H, t, J=7.1 Hz), 4.37 (2H, q, J=7.1Hz), 6.85 (1H, dd, J=4.4, 2.5 Hz), 6.99 (1H, dd, J=4.4, 1.6 Hz), 7.97(1H, dd, J=2.6, 1.6 Hz), 8.32 (1H, s), 12.11 (1H, brs).

e) 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid

A mixture of ethyl4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (15.9 g), a 8 Naqueous sodium hydroxide solution (40 mL) and ethanol (150 mL) washeated and refluxed for 6 hours. The reaction mixture was concentratedunder reduced pressure. To the residue were added 6 N hydrochloric acid(65 mL) and water. The precipitate was collected by filtration, andwashed with water to obtain the title compound (13.40 g).

¹H NMR (300 MHz, DMSO-d₆) δ 6.80 (1H, dd, J=4.4, 2.6 Hz), 6.89 (1H, dd,J=4.4, 1.6 Hz), 7.89 (1H, dd, J=2.6, 1.6 Hz), 8.26 (1H, s).

f) Pyrrolo[1,2-b]pyridazin-4(1H)-one

A mixture of 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid(13.0 g) and DMSO (50 mL) was stirred under a nitrogen atmosphere at150° C. for 1 hour. The reaction mixture was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (8.27 g).

¹H NMR (300 MHz, DMSO-d₆) δ 5.99 (1H, d, J=5.3 Hz), 6.56 (1H, dd, J=4.3,1.7 Hz), 6.69 (1H, dd, J=4.2, 2.6 Hz), 7.71 (1H, dd, J=2.6, 1.7 Hz),7.89 (1H, d, J=5.3 Hz), 11.37 (1H, s).

g) 4-methoxypyrrolo[1,2-b]pyridazine

Cesium carbonate (5.90 g) was added to a solution ofpyrrolo[1,2-b]pyridazin-4(1H)-one (2.00 g) and iodomethane (1.1 mL) inTHF (15 mL) and DMF (5 mL) at 0° C. The mixture was stirred at roomtemperature for 3 hours. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(1.846 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.98 (3H, s), 6.21 (1H, d, J=5.5 Hz), 6.53(1H, dd, J=4.3, 1.7 Hz), 6.72 (1H, dd, J=4.2, 2.7 Hz), 7.76 (1H, dd,J=2.6, 1.7 Hz), 8.05 (1H, d, J=5.4 Hz).

h) 5,7-dibromo-4-methoxypyrrolo[1,2-b]pyridazine

1,3-dibromo-5,5-dimethylhydantoin (3.54 g) was added to a solution of4-methoxypyrrolo[1,2-b]pyridazine (1.83 g) in THF (50 mL) at 0° C. Themixture was stirred at 0° C. for 0.5 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (3.54 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.99 (3H, s), 6.37 (1H, d, J=5.6 Hz), 7.07(1H, s), 8.23 (1H, d, J=5.6 Hz).

i) 5-bromo-4-methoxypyrrolo[1,2-b]pyridazine

n-butyllithium (1.6 M in hexane solution) (7.1 mL) was added dropwise toa solution of 5,7-dibromo-4-methoxypyrrolo[1,2-b]pyridazine (3.52 g) inTHF (70 mL) at −78° C. The mixture was stirred under a nitrogenatmosphere at −78° C. for 0.5 hours. Water was added to the reactionmixture at −78° C., and the temperature was elevated to roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (2.501 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.96 (3H, s), 6.25 (1H, d, J=5.6 Hz), 6.81(1H, dd, J=2.9, 0.3 Hz), 7.79 (1H, d, J=2.9 Hz), 8.07 (1H, d, J=5.5 Hz).

j)1-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[1,2-b]pyridin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of 5-bromo-4-methoxypyrrolo[1,2-b]pyridazine (80 mg),1-(3,5-difluorobenzyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine(107 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.5 mL) and DME (10mL) was stirred under microwave irradiation at 110° C. for 1 hour. Thereaction mixture was diluted with THF. Insolubles were removed byfiltration through Celite, and washed with THF. The filtrate wasconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate). The obtainedproduct was collected by filtration, and washed with ethyl acetate/IPEto obtain the title compound (54 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (3H, s), 3.67 (3H, s), 5.57 (2H, s),6.24 (1H, d, J=5.6 Hz), 6.81-6.96 (3H, m), 7.21 (1H, tt, J=9.4, 2.3 Hz),7.88 (1H, d, J=2.8 Hz), 7.97 (1H, d, J=2.1 Hz), 8.08 (1H, d, J=5.4 Hz),8.49 (1H, d, J=2.1 Hz).

Example 1751-(3-fluorobenzyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) 4-methoxypyrrolo[2,1-f][1,2,4]triazine

A mixture of pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (14 g), DIPEA (18.1mL), N,N-dimethylbenzeneamine (12.56 g), phosphoryl chloride (42.6 mL)and toluene (300 mL) was stirred at 100° C. for 12 hours. The reactionmixture was concentrated under reduced pressure. Sodium methoxide (28%in methanol solution) (140 g) was added to a suspension of the residueand THF (100 mL) at room temperature. The mixture was washed with asaturated aqueous sodium hydrogen carbonate solution at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (12.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.09 (3H, s), 6.73-6.91 (2H, m), 7.94 (1H,dd, J=2.5, 1.6 Hz), 8.19 (1H, s).

b) 5,7-dibromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine

NBS (28.6 g) was added to a solution of4-methoxypyrrolo[2,1-f][1,2,4]triazine (12 g) in THF (200 mL) at roomtemperature. The mixture was stirred under a nitrogen atmosphere at roomtemperature for 1 hour and at 50° C. for 1 hour. The mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solutionat 0° C., and extracted with ethyl acetate. The organic layer was washedwith water and a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was washed with IPE toobtain the title compound (22.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ4.10 (3H, s), 7.22 (1H, s), 8.33 (1H, s).

c) 5-bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine

n-butyllithium (1.6 M in hexane solution) (64.1 mL) was added to asolution of 5,7-dibromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (22.5 g)in THF (450 mL) at −78° C. The mixture was stirred under a nitrogenatmosphere at −78° C. for 30 minutes. Water was added to the reactionmixture at −78° C., and extracted with ethyl acetate. The organic layerwas sequentially washed with water and a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was washed with hexane to obtain the title compound (14.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ4.09 (3H, s), 6.96 (1H, d, J=3.0 Hz), 7.97(1H, d, J=2.8 Hz), 8.19 (1H, s).

d) 6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine

A solution of 5-bromopyridine-2,3-diamine (83.5 g) in acetic acid (500mL) was heated and refluxed for 2 days. The reaction mixture wasconcentrated under reduced pressure. The residue was pulverized withIPE, and dried under reduced pressure to obtain the title compound (93g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.51-2.53 (3H, m), 8.12 (1H, d, J=2.2 Hz),8.31 (1H, d, J=2.2 Hz), 12.96 (1H, brs).

e) 6-bromo-1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine

Potassium hydroxide (1.984 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (2.5 g), 3-fluorobenzylbromide (1.735 mL) and THF (30 mL) at 60° C. The mixture was stirredovernight at 60° C. The reaction solution was cooled to roomtemperature, then poured into water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (1.23 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.54 (3H, s), 5.51 (2H, s), 6.93-7.19 (3H,m), 7.31-7.44 (1H, m), 8.27 (1H, d, J=2.0 Hz), 8.40 (1H, d, J=2.0 Hz).

f)1-(3-fluorobenzyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine (412 mg),a [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloridedichloromethane complex (107 mg), bis(pinacolato)diboron (667 mg),potassium acetate (391 mg), THF (5 mL) and DMSO (0.5 mL) was stirredunder microwave irradiation at 120° C. for 40 minutes. The mixture wasdiluted with a saturated aqueous sodium hydrogen carbonate solution atroom temperature, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over magnesium sulfate, andthen concentrated. The residue was washed with IPE to obtain the titlecompound (108 mg).

MS, found: 286.1.

g)1-(3-fluorobenzyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of 5-bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (52 mg),1-(3-fluorobenzyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine(108 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(14 mg), cesium carbonate (2 M in aqueous solution) (0.215 mL) and DME(1 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The reaction mixture was concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane), and the residue was washed with ethyl acetate to obtainthe title compound (12 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (3H, s), 3.80 (3H, s), 5.58 (2H, s),6.96 (1H, d, J=7.6 Hz), 7.01-7.09 (2H, m), 7.15 (1H, td, J=8.8, 3.0 Hz),7.42 (1H, td, J=8.0, 6.0 Hz), 8.05 (1H, d, J=2.7 Hz), 8.12 (1H, d, J=2.0Hz), 8.21 (1H, s), 8.57 (1H, d, J=2.1 Hz).

Example 176(1-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanola)4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine

A mixture of 5-bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (10 g), a[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloridedichloromethane complex (3.58 g), bis(pinacolato)diboron (17.82 g),potassium acetate (17.21 g), THF (70 mL) and DMSO (10 mL) was stirredunder microwave irradiation at 120° C. for 30 minutes. The mixture wasquenched with a saturated aqueous sodium hydrogen carbonate solution,and extracted with ethyl acetate. The organic layer was washed with asaturated aqueous sodium hydrogen carbonate solution, dried overmagnesium sulfate, and then concentrated. The residue was purified byDiol silica gel column chromatography (ethyl acetate/hexane) to obtainthe title compound (3.96 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.30 (12H, s), 4.06 (3H, s), 6.90-7.01 (1H,m), 7.86-7.96 (1H, m), 8.24 (1H, s).

b) (1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol

A mixture of N3-(3,5-difluorobenzyl)-5-iodopyridine-2,3-diamine (1 g),glycolic acid (5 g) and THF (1 mL) was stirred under microwaveirradiation at 150° C. for 2.5 hours. The mixture was diluted with ethylacetate and water, neutralized with a 8 N aqueous sodium hydroxidesolution, basified with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate) and NHsilica gel column chromatography (ethyl acetate/hexane andmethanol/ethyl acetate) to obtain the title compound (0.65 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.77 (2H, d, J=5.9 Hz), 5.61 (2H, s),5.84-5.95 (1H, m), 6.91-7.04 (2H, m), 7.19 (1H, tt, J=9.3, 2.4 Hz), 8.33(1H, d, J=2.0 Hz), 8.58 (1H, d, J=2.0 Hz).

c)(1-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol

A mixture of(1-(3,5-difluorobenzyl)-6-iodo-1H-imidazo[4,5-b]pyridin-2-yl)methanol(0.915 g),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(2 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(0.137 g), cesium carbonate (2 M in aqueous solution) (3.05 mL) and DME(14 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The reaction mixture was concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the residue was crystallized fromethanol/water to obtain the title compound (0.35 g).

¹H NMR (300 MHz, DMSO-d₆) δ3.79 (3H, s), 4.83 (2H, d, J=3.0 Hz), 5.65(2H, s), 5.91 (1H, brs), 6.95-7.09 (3H, m), 7.15-7.29 (1H, m), 8.02-8.10(2H, m), 8.22 (1H, s), 8.62 (1H, d, J=1.9 Hz).

Example 1796-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea)6-bromo-2-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

Acetic acid (0.4 mL) was added to a solution of2-methyl-2H-pyrazole-3-carbaldehyde (0.8 g) and5-bromopyridine-2,3-diamine (1 g) in THF (20 mL) at room temperature.The mixture was stirred overnight at room temperature. The mixture waspoured into a saturated aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and thenconcentrated to obtain a residue. Sodium borohydride (300 mg) was addedto a solution of the residue in THF (20 mL)/methanol (50 mL) at 0° C.,and the mixture was stirred for 1 hour. The reaction mixture was pouredinto a saturated aqueous ammonium chloride solution, and extracted withethyl acetate. The organic layer was sequentially washed with water anda saturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain a pale yellow solid as5-bromo-N3-((1-methyl-1H-pyrazol-5-yl)methyl)pyridine-2,3-diamine (0.38g). A mixture of the obtained pale yellow solid (300 mg), acetic acid(0.1 mL), DMAP (10 mg), propylphosphonic anhydride (50% in ethyl acetatesolution) (0.938 mL), DIPEA (0.464 mL) and THF (10 mL) was stirred undermicrowave irradiation at 200° C. for 2 hours. The mixture was purifiedby NH silica gel column chromatography (methanol/ethyl acetate) toobtain the title compound (188 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.55 (3H, s), 3.81 (3H, s), 5.63 (2H, s),5.70 (1H, d, J=1.9 Hz), 7.30 (1H, d, J=1.9 Hz), 8.24 (1H, d, J=2.2 Hz),8.42 (1H, d, J=2.2 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine(61 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(151 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(11 mg), cesium carbonate (2 M in aqueous solution) (0.2 mL) and DME (3mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The mixture was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the residue was crystallized fromethanol/ethyl acetate/heptane to obtain the title compound (33 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.60 (3H, s), 3.83 (3H, s), 3.86 (3H, s),5.65 (2H, s), 5.72 (1H, d, J=2.0 Hz), 7.03 (1H, d, J=2.7 Hz), 7.31 (1H,d, J=2.0 Hz), 8.02-8.08 (2H, m), 8.21 (1H, s), 8.56 (1H, d, J=2.0 Hz).

Example 1866-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea) tert-butyl 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate

Sodium hydride (60%, oil) (15.09 g) was added to a solution of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (40 g) in DMF (300 mL) at 0°C. The mixture was stirred at 0° C. for 30 minutes, and tert-butylchloroacetate (40.6 mL) was then added to the mixture. The mixture wasstirred at 0° C. for 1 hour. The reaction was stopped with acetic acid(20 mL) and water at 0° C., and the mixture was extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumhydrogen carbonate solution and a saturated brine, dried over magnesiumsulfate, and then concentrated under reduced pressure to reduce theamount by half. The precipitate was collected by filtration, and washedwith IPE to obtain the title compound (21.11 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43 (9H, s), 2.49 (3H, s), 5.15 (2H, s),8.33 (1H, d, J=2.2 Hz), 8.41 (1H, d, J=2.2 Hz).

b)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole

A solution of tert-butyl2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate (3.00 g) inTFA (10 mL) was stirred at room temperature for 1 hour. The mixture wasconcentrated under reduced pressure to obtain a brown oil. A mixture ofthe obtained brown oil, propylphosphonic anhydride (50% in ethyl acetatesolution) (14.40 mL), (Z)-N′-hydroxyacetimidamide (1.00 g), DIPEA (8 mL)and ethyl acetate (10 mL) was stirred at 80° C. for 4 hours. The residuewas purified by NH silica gel column chromatography (methanol/ethylacetate) to obtain the title compound (1.980 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (3H, s), 2.58 (3H, s), 5.97 (2H, s),8.39 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(680 mg),5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(576 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(105 mg), cesium carbonate (2 M in aqueous solution) (2.336 mL) and DME(14 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The mixture was concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the obtained solid was crystallized fromTHF/ethyl acetate/heptane to obtain the title compound (310 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.29 (3H, s), 2.63 (3H, s), 3.94 (3H, s),6.00 (2H, s), 7.06 (1H, d, J=2.7 Hz), 8.06 (1H, d, J=2.7 Hz), 8.14-8.30(2H, m), 8.59 (1H, d, J=2.1 Hz).

Example 1916-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-thiazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 5-bromo-N3-(thiazol-2-ylmethyl)pyridine-2,3-diamine

Acetic acid (0.4 mL) was added to a solution of2-thiazolecarboxyaldehyde (1.553 mL) and 5-bromopyridine-2,3-diamine (3g) in THF (50 mL) at room temperature. The mixture was stirred overnightat room temperature. The mixture was poured into a saturated aqueoussodium hydrogen carbonate solution, and extracted with ethyl acetate.The organic layer was washed with water and a saturated brine, driedover magnesium sulfate, and then concentrated. Sodium borohydride (4 g)was added to a solution of the residue in THF (20 mL)/methanol (50 mL)at 0° C., and the mixture was stirred for 10 minutes. The reactionmixture was poured into a saturated aqueous ammonium chloride solution,and extracted with ethyl acetate. The organic layer was sequentiallywashed with water and a saturated brine, then dried over magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (2.32 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.65 (2H, d, J=5.9 Hz), 5.81 (2H, s), 6.13(1H, t, J=5.9 Hz), 6.66 (1H, d, J=2.1 Hz), 7.34 (1H, d, J=2.1 Hz), 7.63(1H, d, J=3.3 Hz), 7.77 (1H, d, J=3.3 Hz).

b) 2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiazole

A mixture of 5-bromo-N3-(thiazol-2-ylmethyl)pyridine-2,3-diamine (620mg), acetic acid (0.162 mL), DMAP (20 mg), propylphosphonic anhydride(50% in ethyl acetate solution) (1.918 mL), DIPEA (843 mg) and THF (10mL) was stirred under microwave irradiation at 200° C. for 2 hours. Themixture was purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (540 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 5.92 (2H, s), 7.70-7.81 (2H,m), 8.37-8.45 (2H, m).

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-thiazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiazole (100mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(125 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.3 mL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 1 hour. Themixture was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the obtained solid was crystallized fromethanol/ethyl acetate/heptane to obtain the title compound (47 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 3.88 (3H, s), 5.93 (2H, s),7.05 (1H, d, J 10=2.7 Hz), 7.73 (1H, d, J=3.3 Hz), 7.80 (1H, d, J=3.3Hz), 8.06 (1H, d, J=2.7 Hz), 8.20 (1H, d, J=2.1 Hz), 8.22 (1H, s), 8.57(1H, d, J=2.1 Hz).

Example 1936-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

Potassium hydroxide (2.00 g) was added to a solution of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (5.80 g),2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3.70 g) and TBAI (1.01 g) inTHF (80 mL) at room temperature. The mixture was stirred at 60° C. for 2hours. The mixture was poured into water at room temperature, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate) to obtain thetitle compound (1.550 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.47 (3H, s), 2.61 (3H, s), 5.86 (2H, s),8.36 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=2.2 Hz).

b)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(550 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(450 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(50 mg), cesium carbonate (2 M in aqueous solution) (1.3 mL) and DME (10mL) was stirred under microwave irradiation at 100° C. for 1 hour. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate) and silica gel column chromatography(methanol/ethyl acetate). The obtained solid was crystallized from ethylacetate/ethanol/heptane to obtain the title compound (255 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.47 (3H, s), 2.66 (3H, s), 3.97 (3H, s),5.88 (2H, s), 7.07 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.20 (1H,d, J=2.1 Hz), 8.23 (1H, s), 8.58 (1H, d, J=2.1 Hz).

Example 1996-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxadiazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinea)4-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methyloxazole

Potassium hydroxide (0.287 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (0.361 g),4-(bromomethyl)-2-methyloxazole (0.30 g) and THF (10 mL) at 60° C. Themixture was stirred under a nitrogen atmosphere at 60° C. for 4 hours.The reaction mixture was poured into water, and extracted with ethylacetate. The organic layer was washed with water and a saturated brine,then dried over sodium sulfate, and concentrated under reduced pressure.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (0.124 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (3H, s), 2.67 (3H, s), 5.33 (2H, s),8.09 (1H, s), 8.34-8.37 (1H, m), 8.37-8.40 (1H, m).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxadiazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(120 mg),4-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methyloxazole(79.5 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(13 mg), cesium carbonate (2 M in aqueous solution) (0.200 mL) and DME(3.0 mL) was stirred under microwave irradiation at 100° C. for 15minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (57.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (3H, s), 2.71 (3H, s), 3.96 (3H, s),5.34 (2H, s), 7.05 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.12 (1H,s), 8.17 (1H, d, J=2.1 Hz), 8.23 (1H, s), 8.52 (1H, d, J=2.1 Hz).

Example 2036-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridinea) 5-iodo-N3-((1-methyl-1H-pyrazol-3-yl)methyl)pyridine-2,3-diamine

A mixture of 1-methyl-1H-pyrazole-3-carbaldehyde (0.516 g) and5-iodopyridine-2,3-diamine (1 g), acetic acid (0.256 mL) and THF (20 mL)was stirred at room temperature for 21 hours. The mixture wasneutralized with a saturated aqueous sodium hydrogen carbonate solution,and extracted with THF and ethyl acetate. The organic layer was washedwith a saturated aqueous sodium hydrogen carbonate solution and asaturated brine, dried over magnesium sulfate, and then concentrated toobtain a residue. Sodium borohydride (0.485 g) was added to a solutionof the residue in THF (40 mL)/methanol (10 mL) at 0° C., and the mixturewas stirred at room temperature for 1 hour. The reaction was stoppedwith water and a saturated aqueous ammonium chloride solution at roomtemperature, and the mixture was basified, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/methanol) to obtain the title compound (0.325 g).

MS: [M+H]⁺ 330.1.

b)6-iodo-2-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of5-iodo-N3-((1-methyl-1H-pyrazol-3-yl)methyl)pyridine-2,3-diamine (325.1mg), acetic acid (0.075 mL), DMAP (18 mg), propylphosphonic anhydride(1.7 M in ethyl acetate solution) (0.99 mL), DIPEA (0.346 mL) and THF (3mL) was stirred under microwave irradiation at 160° C. for 1 hour. Theresidue was purified by NH silica gel column chromatography(hexane/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (240 mg).

MS: [M+H]⁺ 354.0.

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine(81 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(175 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(12 mg), cesium carbonate (2 M in aqueous solution) (0.195 mL) and DME(1 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The solvent was distilled off, the residue was then purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with IPE to obtain the title compound (31.3mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.67 (3H, s), 3.76 (3H, s), 3.95 (3H, s),5.41 (2H, s), 6.21 (1H, d, J=2.3 Hz), 7.05 (1H, d, J=2.7 Hz), 7.62 (1H,d, J=2.2 Hz), 8.06 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.1 Hz), 8.22 (1H,s), 8.52 (1H, d, J=2.1 Hz).

Example 2046-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinea) 5-iodo-N3-((2-methylthiazol-4-yl)methyl)pyridine-2,3-diamine

A mixture of 2-methylthiazole-4-carbaldehyde (390 mg) and5-iodopyridine-2,3-diamine (770 mg), acetic acid (0.198 mL) and THF (15mL) was stirred under a nitrogen atmosphere at room temperature for 21hours. The mixture was concentrated under reduced pressure. The residuewas neutralized with a saturated aqueous sodium hydrogen carbonatesolution at 0° C., and extracted with THF and ethyl acetate. The organiclayer was washed with a saturated aqueous sodium hydrogen carbonatesolution and a saturated brine, dried over magnesium sulfate, and thenconcentrated to obtain a residue. Sodium borohydride (311 mg) was addedto a solution of the residue in THF (40 mL)/methanol (10 mL) at 0° C.,and the mixture was stirred at room temperature for 30 min. The reactionwas stopped with water and a saturated aqueous ammonium chloridesolution at room temperature, and the mixture was basified, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol) to obtain the title compound(708 mg).

MS: [M+H]⁺ 347.1.

b)4-((6-iodo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methylthiazole

A mixture of5-iodo-N3-((2-methylthiazol-4-yl)methyl)pyridine-2,3-diamine (300 mg),acetic acid (0.075 mL), DMAP (16 mg), propylphosphonic anhydride (1.7 Min ethyl acetate solution) (0.868 mL), DIPEA (0.304 mL) and THF (2.5 mL)was stirred under microwave irradiation at 160° C. for 1 hour. Theresidue was purified by NH silica gel column chromatography(hexane/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (265 mg).

MS: [M+H]⁺ 370.9.

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-((6-iodo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methylthiazole(94 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(175 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(13 mg), cesium carbonate (2 M in aqueous solution) (0.218 mL) and DME(1 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The solvent was distilled off, the residue was then purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with IPE to obtain the title compound (57.3mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.58 (3H, s), 2.71 (3H, s), 3.93 (3H, s),5.51 (2H, s), 7.04 (1H, d, J=2.7 Hz), 7.52 (1H, s), 8.06 (1H, d, J=2.7Hz), 8.18 (1H, d, J=2.1 Hz), 8.22 (1H, s), 8.53 (1H, d, J=2.1 Hz).

Example 2056-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-oxazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridinea) N-(2-amino-5-iodopyridin-3-yl)oxazole-2-carboxamide

A mixture of 5-iodopyridine-2,3-diamine (1 g), oxazole-2-carboxylic acid(0.482 g), HATU (2.27 g), Et3N (1.78 mL) and DMF (10 mL) was stirred at0° C. for 1 hour, and then stirred overnight at room temperature. Themixture was diluted with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (0.781 g). The title compound was used for the subsequentreaction without being further purified.

MS: [M+H]⁺ 330.9.

b) 5-iodo-N3-(oxazol-2-ylmethyl)pyridine-2,3-diamine

A BH3-THF complex (1M in THF solution) (9 mL) was added dropwise to asolution of N-(2-amino-5-iodopyridin-3-yl)oxazole-2-carboxamide (750 mg)in THF (6 mL) at room temperature. The mixture was stirred under anitrogen atmosphere at 60° C. for 2 hours. The reaction was stopped withwater at room temperature, and the mixture was then acidified with HCl(1 N in aqueous solution). The mixture was stirred at 60° C. for 30minutes. The mixture was neutralized with a saturated aqueous sodiumhydrogen carbonate solution at room temperature, and then extracted withethyl acetate. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (153 mg).

MS: [M+H]⁺ 316.9.

c) 2-((6-iodo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)oxazole

A mixture of 5-iodo-N3-(oxazol-2-ylmethyl)pyridine-2,3-diamine (152.8mg), acetic acid (0.045 mL), DMAP (9 mg), propylphosphonic anhydride(1.7 M in ethyl acetate solution) (0.484 mL), DIPEA (0.195 mL) and THF(1.5 mL) was stirred under microwave irradiation at 160° C. for 1 hour.The residue was purified by NH silica gel column chromatography(hexane/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (99 mg).

MS: [M+H]⁺ 341.0.

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-oxazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-iodo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)oxazole (98mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(210 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(16 mg), cesium carbonate (2 M in aqueous solution) (0.261 mL) and DME(1.2 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The solvent was distilled off, the residue was then purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with IPE to obtain the title compound (44.1mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.64 (3H, s), 3.95 (3H, s), 5.77 (2H, s),7.06 (1H, d, J=2.8 Hz), 7.22 (1H, d, J=0.8 Hz), 8.06 (1H, d, J=2.7 Hz),8.14 (1H, d, J=0.8 Hz), 8.18 (1H, d, J=2.1 Hz), 8.23 (1H, s), 8.57 (1H,d, J=2.0 Hz).

Example 2066-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinea)N-(2-amino-5-iodopyridin-3-yl)-1-methyl-1H-1,2,3-triazole-4-carboxamide

A mixture of 5-iodopyridine-2,3-diamine (1 g),1-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.54 g), HATU (2.27 g),Et3N (1.78 mL) and DMF (10 mL) was stirred at 0° C. for 1 hour, and thenstirred overnight at room temperature. The mixture was diluted with asaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (0.987 g). The titlecompound was used for the subsequent reaction without being furtherpurified.

MS: [M+H]⁺ 344.9.

b)5-iodo-N3-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)pyridine-2,3-diamine

A BH3-THF complex (1M in THF solution) (11 mL) was added dropwise to asolution ofN-(2-amino-5-iodopyridin-3-yl)-1-methyl-1H-1,2,3-triazole-4-carboxamide(985 mg) in THF (8 mL) at room temperature. The mixture was stirredunder a nitrogen atmosphere at 60° C. for 2 hours. The reaction wasstopped with water at room temperature, and the mixture was thenacidified with HCl (1 N in aqueous solution). The mixture was stirred at60° C. for 30 minutes. The mixture was neutralized with a saturatedaqueous sodium hydrogen carbonate solution at room temperature, and thenextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol) to obtain the title compound(682 mg).

MS: [M+H]⁺ 331.0.

c)6-iodo-2-methyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of5-iodo-N3-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)pyridine-2,3-diamine(300 mg), acetic acid (0.084 mL), DMAP (16 mg), propylphosphonicanhydride (1.7 M in ethyl acetate solution) (0.910 mL), DIPEA (0.350 mL)and THF (2.5 mL) was stirred under microwave irradiation at 160° C. for1 hour. The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (167 mg).

MS: [M+H]⁺ 355.0.

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine(97 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(200 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15 mg), cesium carbonate (2 M in aqueous solution) (0.249 mL) and DME(1 mL) was stirred under microwave irradiation at 100° C. for 1 hour,and then stirred at 120° C. for 20 minutes. The solvent was distilledoff, the residue was then purified by NH silica gel columnchromatography (methanol/ethyl acetate), and the obtained solid waswashed with IPE to obtain the title compound (59.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.72 (3H, s), 3.97 (3H, s), 3.99 (3H, s),5.56 (2H, s), 7.07 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.8 Hz), 8.14 (1H,s), 8.21 (1H, d, J=2.0 Hz), 8.23 (1H, s), 8.53 (1H, d, J=2.1 Hz).

Example 2076-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methyloxazole

Potassium hydroxide (3.60 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (4.53 g),5-(bromomethyl)-2-methyloxazole (3.76 g) and THF (100 mL) at roomtemperature. The mixture was stirred under a nitrogen atmosphereovernight at 60° C. Insolubles were removed by filtration through afilter, and the filtrate was concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (2.030 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (3H, s), 2.66 (3H, s), 5.57 (2H, s),7.19 (1H, s), 8.41 (2H, d, J=0.7 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(203 mg),5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methyloxazole(140 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(18 mg), cesium carbonate (2 M in aqueous solution) (0.30 mL) and DME(3.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (78 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.34 (3H, s), 2.70 (3H, s), 3.97 (3H, s),5.58 (2H, s), 7.06 (1H, d, J=2.7 Hz), 7.21 (1H, s), 8.07 (1H, d, J=2.7Hz), 8.20-8.26 (2H, m), 8.54 (1H, d, J=2.1 Hz).

Example 2086-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 6-bromo-2-methyl-1-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (600 mg) was dissolved in THF(20 mL) at 60° C., and potassium hydroxide (476 mg) and2-(bromomethyl)pyrazine (490 mg) were added. The mixture was stirred at60° C. for 16 hours. The reaction solution was cooled to roomtemperature, then diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by NH silica gel column chromatography (ethylacetate/hexane), and the obtained solid was washed with ethylacetate/IPE to obtain the title compound (88.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.59 (3H, s), 5.71 (2H, s), 8.34 (1H, d,J=2.2 Hz), 8.40 (1H, d, J=2.2 Hz), 8.53 (1H, dd, J=2.5, 1.6 Hz), 8.59(1H, d, J=2.5 Hz), 8.82 (1H, d, J=1.5 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine (82mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15.16 mg), cesium carbonate (2 M in aqueous solution) (0.3 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with ethyl acetate/IPE to obtain the titlecompound (45.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 3.83 (3H, s), 5.73 (2H, s),7.03 (1H, d, J=2.7 Hz), 8.05 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.0 Hz),8.21 (1H, s), 8.54 (1H, d, J=2.1 Hz), 8.57-8.62 (2H, m), 8.83 (1H, d,J=1.3 Hz).

Example 2096-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrimidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 6-bromo-2-methyl-1-(pyrimidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (700 mg) was dissolved in THF(20 mL) at 60° C., and potassium hydroxide (741 mg), tetrabutylammoniumiodide (1829 mg) and 2-(chloromethyl)pyrimidine hydrochloride (599 mg)were added. The mixture was stirred at 60° C. for 3 hours. The reactionsolution was cooled to room temperature, then diluted with water, andextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane), and the obtained solid was washedwith ethyl acetate/IPE to obtain the title compound (199 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.50 (3H, s), 5.76 (2H, s), 7.45 (1H, t,J=4.9 Hz), 8.26 (1H, d, J=2.2 Hz), 8.40 (1H, d, J=2.2 Hz), 8.76 (1H, s),8.77 (1H, s).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrimidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-(pyrimidin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine (82mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15.16 mg), cesium carbonate (2 M in aqueous solution) (0.3 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with ethyl acetate/IPE to obtain the titlecompound (33.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H, s), 3.82 (3H, s), 5.77 (2H, s),7.04 (1H, d, J=2.6 Hz), 7.45 (1H, t, J=4.9 Hz), 8.01-8.11 (2H, m), 8.20(1H, s), 8.54 (1H, s), 8.79 (2H, d, J=5.0 Hz).

Example 2106-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 5-iodo-N3-(pyridin-4-ylmethyl)pyridine-2,3-diamine

Acetic acid (0.6 mL) was added to a solution of isonicotinaldehyde (1.34g) and 5-iodopyridine-2,3-diamine (2 g) in THF (20 mL) at roomtemperature. The mixture was stirred at room temperature for 21 hours.The mixture was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added to the residue at 0° C., and the mixturewas extracted with THF/ethyl acetate. The organic layer was washed witha saturated aqueous sodium hydrogen carbonate solution and a saturatedbrine, dried over magnesium sulfate, and then concentrated. Sodiumborohydride (0.644 g) was added to a solution of the residue in THF (30mL)/methanol (3 mL) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. An aqueous ammonium chloride solution was addedto the reaction mixture at 0° C., and the mixture was extracted withethyl acetate. The organic layer was sequentially washed with water anda saturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(933 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.35 (2H, d, J=5.8 Hz), 5.76 (1H, t, J=5.9Hz), 5.81 (2H, s), 6.59 (1H, d, J=1.8 Hz), 7.32-7.35 (2H, m), 7.41 (1H,d, J=1.8 Hz), 8.49-8.54 (2H, m).

b) 6-bromo-2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of 5-iodo-N3-(pyridin-4-ylmethyl)pyridine-2,3-diamine (917mg), acetic acid (0.209 mL), DMAP (51.5 mg), propylphosphonic anhydride(50% in ethyl acetate solution) (2.98 mL), DIPEA (0.982 mL) and THF (15mL) was stirred under microwave irradiation at 160° C. for 1 hour. Themixture was diluted with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane), and the obtained solid was washedwith IPE to obtain the title compound (606 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.51 (3H, s), 5.59 (2H, s), 7.05 (2H, d,J=6.0 Hz), 8.38 (1H, d, J=1.9 Hz), 8.49-8.57 (3H, m).

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine (95mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15.16 mg), cesium carbonate (2 M in aqueous solution) (0.3 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with ethyl acetate/IPE to obtain the titlecompound (46.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.58 (3H, s), 3.74 (3H, s), 5.63 (2H, s),7.05 (1H, d, J=2.6 Hz), 7.10 (2H, d, J=5.7 Hz), 8.04 (1H, d, J=2.6 Hz),8.09 (1H, d, J=1.8 Hz), 8.20 (1H, s), 8.53-8.60 (3H, m).

Example 2116-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 6-bromo-2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridine

6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (600 mg) was dissolved in THF(20 mL) at 60° C., and potassium hydroxide (635 mg) and3-(bromomethyl)pyridine (787 mg) were added. The mixture was stirred at60° C. for 3 hours. The reaction solution was cooled to roomtemperature, then diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified by NH silica gel column chromatography (ethylacetate/hexane), and the obtained solid was washed with ethylacetate/IPE to obtain the title compound (382 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.58 (3H, s), 5.58 (2H, s), 7.36 (1H, ddd,J=7.9, 4.8, 0.8 Hz), 7.52 (1H, dt, J=8.2, 1.9 Hz), 8.36 (1H, d, J=2.2Hz), 8.42 (1H, d, J=2.2 Hz), 8.49-8.55 (2H, m).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridine (82mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15.16 mg), cesium carbonate (2 M in aqueous solution) (0.3 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was diluted with water, and extracted with ethyl acetate.The organic layer was washed with a saturated brine, dried overmagnesium sulfate, and then concentrated. The residue was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with ethyl acetate/IPE to obtain the titlecompound (49.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 3.82 (3H, s), 5.61 (2H, s),7.05 (1H, d, J=2.8 Hz), 7.39 (1H, dd, J=7.6, 4.5 Hz), 7.53-7.61 (1H, m),8.05 (1H, d, J=2.7 Hz), 8.17 (1H, d, J=2.0 Hz), 8.21 (1H, s), 8.52 (1H,dd, J=4.7, 1.5 Hz), 8.56 (2H, d, J=1.9 Hz).

Example 2126-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2-oxadiazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridinea)3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methylisoxazole

Potassium hydroxide (1.081 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (1.361 g),3-(bromomethyl)-5-methylisoxazole (1.13 g) and THF (30 mL) at roomtemperature. The mixture was stirred under a nitrogen atmosphere at 60°C. for 4 hours. The reaction mixture was poured into water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with water and a saturated brine, then dried over sodium sulfate,and concentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane), and the residuewas washed with IPE to obtain the title compound (0.819 g).

¹H NMR (300 MHz, DMSO-d₆) δ2.35 (3H, d, J=0.8 Hz), 2.59 (3H, s), 5.58(2H, s), 6.21 (1H, d, J=0.8 Hz), 8.34 (1H, d, J=2.2 Hz), 8.42 (1H, d,J=2.2 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2-oxadiazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(144 mg),3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methylisoxazole(100 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(22 mg), cesium carbonate (2 M in aqueous solution) (0.330 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The reaction mixture was purified by silica gel columnchromatography (methanol/ethyl acetate), and the residue was washed withethyl acetate/heptane to obtain the title compound (63.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.35 (3H, s), 2.64 (3H, s), 3.94 (3H, s),5.59 (2H, s), 6.21 (1H, s), 7.07 (1H, d, J=2.8 Hz), 8.07 (1H, d, J=2.6Hz), 8.16 (1H, d, J=1.9 Hz), 8.23 (1H, s), 8.56 (1H, d, J=1.7 Hz).

Example 2136-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methylthiazole

Potassium hydroxide (0.709 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (0.893 g),5-(bromomethyl)-2-methylthiazole (0.809 g) and THF (20 mL) at roomtemperature. The mixture was stirred under a nitrogen atmosphere at 60°C. for 4 hours. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, then dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(0.0953 g).

¹H NMR (300 MHz, CDCl₃) δ 2.67 (3H, s), 2.69-2.72 (3H, m), 5.40 (2H, s),7.52 (1H, s), 7.73 (1H, d, J=2.1 Hz), 8.55 (1H, d, J=2.1 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(131 mg),5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-2-methylthiazole(95.3 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20.0 mg), cesium carbonate (2 M in aqueous solution) (0.300 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The residue was purified by silica gel column chromatography(methanol/ethyl acetate), and the residue was washed with ethylacetate/heptane to obtain the title compound (51.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H, s), 2.66 (3H, s), 3.95 (3H, s),5.73 (2H, s), 7.05 (1H, d, J=2.7 Hz), 7.76 (1H, s), 8.07 (1H, d, J=2.7Hz), 8.21-8.27 (2H, m), 8.55 (1H, d, J=2.0 Hz).

Example 2146-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridinea)3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,2,4-oxadiazole

Potassium hydroxide (1.270 g) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (1.600 g),3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (1 g), TBAI (2.79 g) and THF(10 mL) at 60° C. The mixture was stirred under a nitrogen atmosphere at60° C. for 2 hours. The mixture was poured into water at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with water and a saturated brine, dried over magnesium sulfate,and concentrated under reduced pressure. The residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (0.430 g).

¹H NMR (300 MHz, DMSO-d₆) δ2.54 (3H, s), 2.60 (3H, s), 5.73 (2H, s),8.33 (1H, d, J=2.2 Hz), 8.43 (1H, d, J=2.2 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(595 mg),3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,2,4-oxadiazole(420 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(45.8 mg), cesium carbonate (2 M in aqueous solution) (2.045 mL) and DME(12 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The mixture was poured into ice water at room temperature, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain a solid. The obtainedsolid was washed with ethyl acetate/IPE to obtain the title compound(171 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.55 (3H, s), 2.66 (3H, s), 3.97 (3H, s),5.73 (2H, s), 7.06 (1H, d, J=2.8 Hz), 8.06 (1H, d, J=2.7 Hz), 8.17 (1H,d, J=2.0 Hz), 8.23 (1H, s), 8.57 (1H, d, J=2.1 Hz).

Example 2156-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methylisoxazole

Potassium hydroxide (1.588 g) was added to a solution of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (2 g),5-(bromomethyl)-3-methylisoxazole (1.8 g) and TBAI (3.48 g) in THF at60° C. The mixture was stirred under a nitrogen atmosphere at 60° C. for2 hours. The reaction mixture was poured into water, and extracted withethyl acetate. The organic layer was sequentially washed with water anda saturated brine, then dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (hexane/ethyl acetate) to obtain the title compound (0.89g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (3H, s), 2.63 (3H, s), 5.71 (2H, s),6.38 (1H, s), 8.40-8.42 (1H, m), 8.42-8.46 (1H, m).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methylisoxazole(644.5 mg),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(502 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(129 mg), cesium carbonate (2 M in aqueous solution) (1.825 mL) and DME(12 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the residue was crystallized fromethanol/water to obtain the title compound (138 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.19 (3H, s), 2.66 (3H, s), 3.96 (3H, s),5.72 (2H, s), 6.40 (1H, s), 7.07 (1H, d, J=2.8 Hz), 8.07 (1H, d, J=2.7Hz), 8.21-8.25 (2H, m), 8.57 (1H, d, J=2.1 Hz).

Example 220 b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole

Potassium hydroxide (600 mg) was added to a mixture of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (720 mg),2-(chloromethyl)-5-methyl-1,3,4-thiadiazole (550 mg), TBAI (1254 mg) andTHF (10 mL) at room temperature. The mixture was stirred at 60° C. for 2hours. The mixture was poured into water at room temperature, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(182 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 2.68 (3H, s), 6.00 (2H, s),8.39-8.46 (2H, m).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole(80 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(11 mg), cesium carbonate (2 M in aqueous solution) (0.250 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate) to obtain a solid. The obtained solid wascrystallized from ethanol/THF/heptane to obtain the title compound (33.5mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 2.67 (3H, s), 3.94 (3H, s),6.02 (2H, s), 7.05 (1H, d, J=2.8 Hz), 8.07 (1H, d, J=2.8 Hz), 8.20-8.25(2H, m), 8.58 (1H, d, J=2.0 Hz).

Example 2296-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridinea) 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetonitrile

A mixture of potassium tert-butoxide (11 g),6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (20 g) and THF (200 mL) wasstirred at 50° C. for 30 minutes. To the mixture was added dropwise asolution of bromoacetonitrile (7.00 mL) in THF (20 mL) at 50° C. Themixture was stirred at 50° C. for 2 hours, and then cooled to 5° C. Themixture was diluted with water (100 mL), and stirred at 5° C. for 30minutes. The precipitate was collected by filtration, and washed withwater (100 mL) and ethyl acetate (50 mL) to obtain a solid (13.3 g). Asuspension of the obtained solid (13.3 g) in ethyl acetate (260 mL) wasstirred at 70° C. for 60 minutes. The suspension was cooled to 40° C.,and the precipitate was then collected by filtration, and washed withethyl acetate (100 mL) to obtain the title compound (7.52 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 5.63 (2H, s), 8.45-8.47 (1H,m), 8.47-8.50 (1H, m).

b) 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)ethanethioamide

Diethyl phosphorodithioic acid (3.00 mL) was added to a solution of2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetonitrile (2.40 g)in THF (40 mL)/water (4 mL) at room temperature. The mixture was stirredat 70° C. for 3 hours. The mixture was cooled, and the residue waspurified by NH silica gel column chromatography (methanol/ethyl acetate)to obtain the title compound (2.150 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.50 (3H, s), 5.16 (2H, s), 8.20 (1H, d,J=2.2 Hz), 8.38 (1H, d, J=2.2 Hz), 9.51 (1H, brs), 9.94 (1H, brs).

c)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-thiadiazole

N,N-dimethylacetamide dimethylacetal (900 μL) was added to a suspensionof 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)ethanethioamide(1.40 g) in acetonitrile (50 mL) at room temperature. The mixture wasstirred at 40° C. for 3 hours, and then concentrated under reducedpressure to obtain a brown oil. Pyridine (1.00 mL) was added to asolution of the obtained oil in methanol (10 mL) at 0° C. The mixturewas stirred at 0° C. for 10 minutes, and a solution ofhydroxylamine-O-sulfonic acid (600 mg) in methanol (15 mL) was thenadded dropwise to the mixture. The mixture was stirred overnight at roomtemperature. The precipitate was collected by filtration, and washedwith IPA and water to obtain the title compound (644 mg). The filtratewas poured into a saturated aqueous sodium hydrogen carbonate solution,and extracted twice with ethyl acetate. The organic layer was washedwith water and a saturated brine, dried over magnesium sulfate, and thenconcentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (660mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.51 (3H, s), 2.62 (3H, s), 6.08 (2H, s),8.40-8.42 (1H, m), 8.43-8.45 (1H, m).

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(3-methyl-1,2,4-thiadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(1867 mg),5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-thiadiazole(550 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(57.1 mg), cesium carbonate (2 M in aqueous solution) (2.54 mL) and DME(12 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The mixture was poured into ice water at room temperature, andextracted with ethyl acetate. The organic layer was washed with waterand a saturated brine, dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain a solid. The obtainedsolid was washed with ethyl acetate/IPE to obtain the title compound(210 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.54 (3H, s), 2.66 (3H, s), 3.86 (3H, s),6.11 (2H, s), 7.05 (1H, d, J=2.8 Hz), 8.06 (1H, d, J=2.8 Hz), 8.15-8.28(2H, m), 8.58 (1H, d, J=2.1 Hz).

Example 2306-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinea)6-bromo-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinedi-TFA salt

6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (700 mg) was dissolved in THF(20 mL) at 60° C., and KOH (742 mg), TBAI (123 mg) and4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride (663 mg) were addedat 60° C. The mixture was stirred at 60° C. for 2 hours. The mixture wasdiluted with water at room temperature, and extracted with ethylacetate. The organic layer was washed with a saturated brine, then driedover magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by NH silica gel column chromatography (ethylacetate/methanol), the obtained solid was further fractionated by HPLC(C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)),and the fraction was concentrated to obtain the title compound (305 mg).

MS: [M+H]⁺ 306.0.

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-b]pyridinedi-TFA salt (200 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(140 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(21 mg), cesium carbonate (2 M in aqueous solution) (0.330 mL) and DME(1.5 mL) was stirred under microwave irradiation at 100° C. for 1 hour,and then stirred at 120° C. for 20 minutes. The mixture was purified byNH silica gel column chromatography (methanol/ethyl acetate), and theobtained solid was washed with IPE to obtain the title compound (90 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (3H, s), 3.75 (3H, s), 3.93 (3H, s),5.32 (2H, s), 7.07 (1H, d, J=2.8 Hz), 7.49 (1H, s), 7.74 (1H, s), 8.07(1H, d, J=2.8 Hz), 8.18 (1H, d, J=2.0 Hz), 8.23 (1H, s), 8.52 (1H, d,J=2.0 Hz).

Example 2316-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridinea)N-(2-amino-5-bromopyridin-3-yl)-1-methyl-1H-1,2,4-triazole-3-carboxamide

A mixture of 5-bromopyridine-2,3-diamine (1.5 g),1-methyl-1H-1,2,4-triazole-3-carboxylic acid (1.02 g), HATU (4.26 g),Et3N (3.4 mL) and DMF (16 mL) was stirred overnight at room temperature.The mixture was diluted with a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, then dried over magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/methanol) to obtain thetitle compound (0.663 g). The title compound was used for the subsequentreaction without being further purified.

MS: [M+H]⁺ 297.0.

b)5-bromo-N3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)pyridine-2,3-diamine

A BH3-THF complex (1M in THF solution) (7.7 mL) was added dropwise to asolution ofN-(2-amino-5-bromopyridin-3-yl)-1-methyl-1H-1,2,4-triazole-3-carboxamide(662.7 mg) in THF (6 mL) at room temperature. The mixture was stirredunder a nitrogen atmosphere at 60° C. for 2 hours. The reaction wasstopped with water at room temperature, and the mixture was thenacidified with HCl (1 N in aqueous solution). The mixture was stirred at60° C. for 30 minutes. The mixture was neutralized with a saturatedaqueous sodium hydrogen carbonate solution at room temperature, and thenextracted with ethyl acetate. The organic layer was washed with asaturated brine, then dried over magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/methanol) to obtain the title compound(348 mg).

MS: [M+H]⁺ 283.1.

c)6-bromo-2-methyl-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of5-bromo-N3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)pyridine-2,3-diamine(348 mg), acetic acid (0.09 mL), DMAP (22 mg), propylphosphonicanhydride (1.7 M in ethyl acetate solution) (1.1 mL), DIPEA (0.43 mL)and THF (2.5 mL) was stirred under microwave irradiation at 160° C. for50 minutes. The residue was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(301 mg).

MS: [M+H]⁺ 307.0.

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-bromo-2-methyl-1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-imidazo[4,5-b]pyridine(90 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(120 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(18 mg), cesium carbonate (2 M in aqueous solution) (0.285 mL) and DME(1.5 mL) was stirred under microwave irradiation at 120° C. for 1 hour.The mixture was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (45.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (3H, s), 3.80 (3H, s), 3.97 (3H, s),5.53 (2H, s), 7.06 (1H, d, J=2.7 Hz), 8.06 (1H, d, J=2.7 Hz), 8.14 (1H,d, J=2.1 Hz), 8.22 (1H, s), 8.42 (1H, s), 8.54 (1H, d, J=2.0 Hz).

Example 2376-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridinea) 5-iodo-N3-(pyridin-2-ylmethyl)pyridine-2,3-diamine

Acetic acid (0.657 mL) was added to a solution of picolinaldehyde (0.476mL) and 5-bromopyridine-2,3-diamine (1.07 g) in THF (10 mL) at roomtemperature. The mixture was stirred overnight at room temperature. Themixture was poured into a saturated aqueous sodium hydrogen carbonatesolution, and extracted twice with ethyl acetate. The organic layerswere combined, washed with a saturated brine, dried over magnesiumsulfate, and then concentrated to obtain a residue. To a solution of theresidue in methanol (10 mL) was added sodium borohydride (0.431 g) atroom temperature, and the mixture was stirred overnight. The reactionmixture was poured into water, and extracted twice with ethyl acetate.The organic layers were combined, then washed with a saturated brine,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane/methanol) to obtain the title compound (0.26 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.37 (2H, d, J=5.8 Hz), 5.72-5.90 (3H, m),6.63 (1H, d, J=1.9 Hz), 7.28 (1H, ddd, J=7.5, 4.8, 1.1 Hz), 7.35 (1H, d,J=7.8 Hz), 7.40 (1H, d, J=1.9 Hz), 7.77 (1H, td, J=7.7, 1.8 Hz),8.51-8.58 (1H, m).

b) 6-bromo-2-methyl-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of 5-iodo-N3-(pyridin-2-ylmethyl)pyridine-2,3-diamine (0.26g), acetic acid (0.055 mL), DMAP (4.87 mg), propylphosphonic anhydride(50% in ethyl acetate solution) (0.703 mL), DIPEA (0.278 mL) and THF (3mL) was stirred under microwave irradiation at 180° C. for 4 hours. Themixture was purified by NH silica gel column chromatography(hexane/ethyl acetate) to obtain the title compound (0.154 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.56 (3H, s), 5.60 (2H, s), 7.27-7.39 (2H,m), 7.81 (1H, td, J=7.7, 1.8 Hz), 8.38 (1H, d, J=1.9 Hz), 8.45-8.50 (2H,m).

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of6-iodo-2-methyl-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridine (153.6mg),4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(127 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(31.1 mg), cesium carbonate (2 M in aqueous solution) (0.439 mL) and DME(2 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was purified by NH silica gel column chromatography(methanol/ethyl acetate), and the residue was crystallized fromethanol/water to obtain the title compound (74.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 3.80 (3H, s), 5.63 (2H, s),7.04 (1H, d, J=2.8 Hz), 7.29-7.37 (2H, m), 7.82 (1H, td, J=7.7, 1.8 Hz),8.04 (1H, d, J=2.8 Hz), 8.11 (1H, d, J=2.1 Hz), 8.20 (1H, s), 8.49-8.53(1H, m), 8.54 (1H, d, J=2.1 Hz).

Example 2421-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea) methyl 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate

A mixture of potassium tert-butoxide (11.1 g),6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (20.0 g) and THF (200 mL) wasstirred at 50° C. for 20 minutes. Methyl 2-bromoacetate (17.4 g) wasadded to the mixture. The mixture was stirred at 50° C. for 1 hour. Thereaction was stopped with acetic acid/water (1/10) at 0° C., and themixture was diluted with ethyl acetate (100 mL) and a saturated aqueoussodium hydrogen carbonate solution (100 mL). The precipitate wascollected by filtration, and the obtained solid was washed with water(100 mL) and ethyl acetate (50 mL) to obtain the title compound (13.10g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.52 (3H, s), 3.73 (3H, s), 5.27 (2H, s),8.33 (1H, d, J=2.2 Hz), 8.41 (1H, d, J=2.2 Hz).

b) 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide

A suspension of methyl2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate (6.43 g) inethanol (130 mL)/water (13 mL) was stirred at 70° C. for 10 minutes.Hydrazine monohydrate (10 mL) was added to the mixture, and the mixturewas stirred at 70° C. for 1 hour, and then stirred at 0° C. for 2 hours.The precipitate was collected by filtration, and washed with ethanol (30mL) to obtain the title compound (5.17 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.53 (3H, s), 4.36 (2H, brs), 4.87 (2H, s),8.22 (1H, d, J=2.2 Hz), 8.39 (1H, d, J=2.2 Hz), 9.49 (1H, brs).

c)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(difluoromethyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (8.0 mL) wasadded to a suspension of triethylamine (3.00 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (1.70g) and difluoroacetic acid (500 μL) in ethyl acetate (55 mL) at roomtemperature. The mixture was stirred at 50° C. for 20 minutes, and thenstirred under microwave irradiation at 140° C. for 60 minutes.Insolubles were removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain a solid. The obtainedsolid was washed with ethyl acetate/hexane to obtain the title compound(0.730 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 5.99 (2H, s), 7.19-7.73 (1H,m), 8.39 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

d)1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(900 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(difluoromethyl)-1,3,4-oxadiazole(305 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(30 mg), cesium carbonate (2 M in aqueous solution) (850 μL) and DME (8mL) was stirred under microwave irradiation at 100° C. for 1 hour. Theresidue was purified by silica gel column chromatography (methanol/ethylacetate) to obtain a solid. The obtained solid was crystallized fromethanol/water to obtain the title compound (88 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.67 (3H, s), 3.96 (3H, s), 6.02 (2H, s),7.05 (1H, d, J=2.7 Hz), 7.25-7.69 (1H, m), 8.07 (1H, d, J=2.7 Hz),8.21-8.25 (2H, m), 8.59 (1H, d, J=2.1 Hz).

Example 2431-((5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1,1-difluoroethyl)-1,2,4-oxadiazole

Sodium carbonate (1.266 g) was added to a mixture of hydroxylaminemonohydrochloride (0.850 g) and water (5.0 ml) at room temperature. Themixture was stirred for 10 minutes. Thereafter, to the mixture was addeda mixture of2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetonitrile (2.00 g)and ethanol (30 ml), and the resulting mixture was stirred under anitrogen atmosphere at 70° C. for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and diluted with water. Insolubleswere collected by filtration, and washed with IPE to obtain a brownsolid (1.589 g) as2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)-N′-hydroxyacetimidamide.The obtained solid (500 mg) was added to a mixture of DIEA (0.867 ml),2,2-difluoropropanoic acid (140 mg), propylphosphonic anhydride (50% inethyl acetate solution) (1.477 ml) and ethyl acetate (4 ml) at roomtemperature, and the resulting mixture was stirred at room temperaturefor 2 days. The reaction mixture was concentrated under reducedpressure, and the residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (77mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (3H, t, J=19.8 Hz), 2.62 (3H, s), 5.88(2H, s), 8.37 (1H, d, J=2.1 Hz), 8.44 (1H, d, J=2.1 Hz).

b)1-((5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of3-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1,1-difluoroethyl)-1,2,4-oxadiazole(77.0 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(99 mg)bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15 mg), cesium carbonate (2 M in aqueous solution) (0.20 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 30minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (19.00 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.14 (3H, t, J=19.8 Hz), 2.67 (3H, s), 3.96(3H, s), 5.90 (2H, s), 7.06 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz),8.20-8.25 (2H, m), 8.58 (1H, d, J=2.0 Hz).

Example 2506-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(trifluoromethyl)-1,3,4-oxadiazole

A mixture of potassium tert-butoxide (2.80 g),6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (5.00 g) and THF (60 mL) wasstirred at 45° C. for 30 minutes. To the mixture were added TBAI (8.71g) and 2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole (5.00 g),and the resulting mixture was stirred at 45° C. for 1 hour. The mixturewas neutralized with aqueous acetic acid, and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodiumhydrogen carbonate solution and a saturated brine, dried over magnesiumsulfate, and then concentrated under reduced pressure. The residue waspurified by NH silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (0.094 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.64 (3H, s), 6.00 (2H, s), 8.37 (1H, d,J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(100 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(trifluoromethyl)-1,3,4-oxadiazole(94 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(10 mg), cesium carbonate (2 M in aqueous solution) (250 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate) to obtain a solid. The obtained solid wascrystallized from ethyl acetate/ethanol/heptane to obtain the titlecompound (18.50 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (3H, s), 3.97 (3H, s), 6.02 (2H, s),7.05 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.19-8.27 (2H, m), 8.59(1H, d, J=2.1 Hz).

Example 2521-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-ethyl-1,3,4-oxadiazole

A solution of tert-butyl2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate (580 mg) inTFA (5 mL) was stirred at room temperature for 1 hour, and concentratedunder reduced pressure. To a solution of the residue in ethyl acetate (6ml) were added TEA (1.239 ml), propionohydrazide (220 mg) andpropylphosphonic anhydride (50% in ethyl acetate solution) (3.70 ml) atroom temperature, and the mixture was stirred overnight at 80° C., andstirred under microwave irradiation at 150° C. for 2 hours. The residuewas purified by NH silica gel column chromatography (methanol/ethylacetate) to obtain the title compound (325 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.23 (3H, t, J=7.6 Hz), 2.61 (3H, s), 2.83(2H, q, J=7.6 Hz), 5.86 (2H, s), 8.36 (1H, d, J=2.2 Hz), 8.44 (1H, d,J=2.2 Hz).

b)1-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-ethyl-1,3,4-oxadiazole(100 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(149 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(22 mg), cesium carbonate (2 M in aqueous solution) (0.24 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane acetate and methanol/ethylacetate), and the residue was crystallized from ethanol/ethylacetate/heptane to obtain the title compound (66.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (3H, t, J=7.5 Hz), 2.66 (3H, s),2.78-2.89 (2H, m), 3.97 (3H, s), 5.88 (2H, s), 7.06 (1H, d, J=2.8 Hz),8.07 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=2.1 Hz), 8.23 (1H, s), 8.58 (1H,d, J=1.9 Hz).

Example 2531-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-cyclopropyl-1,3,4-oxadiazole

A solution of tert-butyl2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetate (500 mg) inTFA (5.0 mL) was stirred at room temperature for 1 hour, andconcentrated under reduced pressure. To a solution of the residue inethyl acetate (2 ml) were added TEA (1.068 ml),cyclopropanecarbohydrazide (220 mg) and propylphosphonic anhydride (50%in ethyl acetate solution) (3.19 ml) at room temperature, and themixture was stirred at room temperature for 1 hour, and stirred undermicrowave irradiation at 150° C. for 2 hours. The residue was purifiedby NH silica gel column chromatography (methanol/ethyl acetate) toobtain the title compound (61.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92-0.99 (2H, m), 1.07-1.15 (2H, m),2.15-2.25 (1H, m), 2.60 (3H, s), 5.80 (2H, s), 8.35 (1H, d, J=2.2 Hz),8.44 (1H, d, J=2.2 Hz).

b)1-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-cyclopropyl-1,3,4-oxadiazole(61.2 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(88 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(13 mg), cesium carbonate (2 M in aqueous solution) (0.15 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane acetate and methanol/ethylacetate), and the residue was crystallized from ethanol/ethylacetate/heptane to obtain the title compound (28.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91-1.00 (2H, m), 1.04-1.16 (2H, m),2.15-2.25 (1H, m), 2.65 (3H, s), 3.97 (3H, s), 5.83 (2H, s), 7.06 (1H,d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.19 (1H, d, J=2.1 Hz), 8.23 (1H,s), 8.58 (1H, d, J=2.1 Hz).

Example 2671-((5-isopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-isopropyl-1,3,4-oxadiazole

A mixture of isobutyric acid (180 μL), TEA (1.10 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (450mg), propylphosphonic anhydride (50% in ethyl acetate solution) (3.30ml) and ethyl acetate (2.0 ml) was stirred under microwave irradiationat 150° C. for 30 minutes. The reaction mixture was purified by NHsilica gel column chromatography (methanol/ethyl acetate) to obtain thetitle compound (337 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (6H, d, J=7.0 Hz), 2.61 (3H, s),3.10-3.24 (1H, m), 5.86 (2H, s), 8.36 (1H, d, J=2.2 Hz), 8.44 (1H, d,J=2.2 Hz).

b)1-((5-isopropyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-isopropyl-1,3,4-oxadiazole(100 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(143 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.24 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (61.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.26 (6H, d, J=6.9 Hz), 2.66 (3H, s),3.12-3.23 (1H, m), 3.96 (3H, s), 5.88 (2H, s), 7.06 (1H, d, J=2.7 Hz),8.07 (1H, d, J=2.7 Hz), 8.20 (1H, d, J=2.0 Hz), 8.23 (1H, s), 8.58 (1H,d, J=2.0 Hz).

Example 2681-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-cyclobutyl-1,3,4-oxadiazole

A mixture of cyclobutanecarboxylic acid (130 μL), TEA (0.73 ml),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (300mg), propylphosphonic anhydride (50% in ethyl acetate solution) (2.10ml) and ethyl acetate (2.0 ml) was stirred under microwave irradiationat 150° C. for 30 minutes. The reaction mixture was purified by NHsilica gel column chromatography (methanol/ethyl acetate), and theresidue was washed with ethyl acetate/heptane to obtain the titlecompound (210 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (2H, s), 2.20-2.41 (4H, m), 2.61 (3H,s), 3.67-3.82 (1H, m), 5.85 (2H, s), 8.37 (1H, d, J=2.2 Hz), 8.44 (1H,d, J=2.2 Hz).

b)1-((5-cyclobutyl-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-cyclobutyl-1,3,4-oxadiazole(100 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(138 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.24 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (67.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.84-2.11 (2H, m), 2.21-2.39 (4H, m), 2.66(3H, s), 3.66-3.82 (1H, m), 3.96 (3H, s), 5.88 (2H, s), 7.06 (1H, d,J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.20 (1H, d, J=2.1 Hz), 8.23 (1H, s),8.58 (1H, d, J=2.1 Hz).

Example 2691-((5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazole

A mixture of 3,3-difluorocyclobutanecarboxylic acid (180 mg), TEA (0.73ml), 2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide(300 mg), propylphosphonic anhydride (50% in ethyl acetate solution)(2.10 ml) and ethyl acetate (2.0 ml) was stirred under microwaveirradiation at 150° C. for 20 minutes. The reaction mixture was purifiedby NH silica gel column chromatography (methanol/ethyl acetate) toobtain the title compound (209 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (3H, s), 2.83-3.21 (4H, m), 3.62-3.80(1H, m), 5.86 (2H, s), 8.36 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=2.2 Hz).

b)1-((5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazole(100 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(315 mg)bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.20 mL) and DME(2.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (61.1 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.67 (3H, s), 2.85-3.17 (4H, m), 3.72 (1H,d, J=7.9 Hz), 3.97 (3H, s), 5.89 (2H, s), 7.06 (1H, d, J=2.8 Hz), 8.07(1H, d, J=2.8 Hz), 8.21 (1H, d, J=2.1 Hz), 8.23 (1H, s), 8.58 (1H, d,J=2.1 Hz).

Example 2736-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,2-dimethyl-1H-imidazo[4,5-b]pyridinea) 6-bromo-1,2-dimethyl-1H-imidazo[4,5-b]pyridine

Potassium hydroxide (15.88 g) was added to a solution of6-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (15 g) and iodomethane (5.31mL) in THF (150 mL) at room temperature. Under a nitrogen atmosphere,the mixture was stirred at 60° C. for 3 hours. The reaction mixture waspoured into hydrochloric acid (1N in aqueous solution) at roomtemperature, and extracted with ethyl acetate. The organic layer waswashed with water and a saturated brine, dried over magnesium sulfate,and then concentrated. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (8.3g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.57 (3H, s), 3.75 (3H, s), 8.29 (1H, d,J=2.26 Hz), 8.37 (1H, d, J=2.26 Hz).

b)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1,2-dimethyl-1H-imidazo[4,5-b]pyridine

A mixture of 6-bromo-1,2-dimethyl-1H-imidazo[4,5-b]pyri dine (70 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(135 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(10.41 mg), cesium carbonate (2 M in aqueous solution) (0.464 mL) andDME (12 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The reaction mixture was poured into ice water at roomtemperature, and extracted with ethyl acetate. The organic layer wassequentially washed with water and a saturated brine, then dried overmagnesium sulfate, and concentrated under reduced pressure. The mixturewas purified by NH silica gel column chromatography (methanol/ethylacetate), and the residue was washed with ethyl acetate/IPE to obtainthe title compound (27 mg).

¹H NMR (300 MHz, DMSO-d₆) δ2.60 (3H, s), 3.80 (3H, s), 4.02 (3H, s),7.08 (1H, d, J 5=2.7 Hz), 7.99-8.12 (2H, m), 8.23 (1H, s), 8.53 (1H, d,J=2.1 Hz).

Example 2741-((5-(1,1-(difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1,1-difluoroethyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (2.57 mL) wasadded to a suspension of triethylamine (0.859 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (350mg) and 2,2-difluoropropanoic acid (200 mg) in ethyl acetate (2 mL) atroom temperature. The mixture was stirred under microwave irradiation at150° C. for 30 minutes. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (135mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (3H, t, J=19.5 Hz), 2.63 (3H, s), 5.97(2H, s), 8.39 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

b)1-((5-(1,1-difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(135 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1,1-difluoroethyl)-1,3,4-oxadiazole(130 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(15 mg), cesium carbonate (2 M in aqueous solution) (300 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by NH silica gel column chromatography(methanol/ethyl acetate) and silica gel column chromatography(methanol/ethyl acetate) to obtain a solid. The solid was purified bypreparative HPLC (C18, mobile phase: water/acetonitrile (10 mM ammoniumhydrogen carbonate-containing system)), and the target fraction wasconcentrated under reduced pressure, and then crystallized fromethanol/water to obtain the title compound (38.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (3H, t, J=19.5 Hz), 2.67 (3H, s), 3.96(3H, s), 6.01 (2H, s), 7.05 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz),8.23 (1H, s), 8.24 (1H, d, J=2.1 Hz), 8.59 (1H, d, J=2.1 Hz).

Example 2761-((5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (2.200 mL)was added to a suspension of triethylamine (0.736 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (300mg) and 2,2-difluorocyclopropanecarboxylic acid (150 mg) in ethylacetate (6 mL) at room temperature. The mixture was stirred undermicrowave irradiation at 150° C. for 30 minutes. The residue waspurified by NH silica gel column chromatography (methanol/ethyl acetate)to obtain the title compound (230 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.04-2.23 (1H, m), 2.25-2.44 (1H, m), 2.61(3H, s), 3.41-3.60 (1H, m), 5.89 (2H, s), 8.37 (1H, d, J=2.1 Hz), 8.44(1H, d, J=2.1 Hz).

b)1-((5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(550 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazole(220 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (300 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by silica gel column chromatography (ethylacetate/hexame and methanol/ethyl acetate) to obtain the title compound(98 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.09-2.23 (1H, m), 2.28-2.39 (1H, m), 2.66(3H, s), 3.42-3.57 (1H, m), 3.96 (3H, s), 5.92 (2H, s), 7.06 (1H, d,J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.21 (1H, d, J=2.1 Hz), 8.23 (1H, s),8.58 (1H, d, J=2.1 Hz).

Example 2771-((5-(2-fluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2-fluoropropan-2-yl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (2.200 mL)was added to a suspension of triethylamine (0.736 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (300mg) and 2-fluoro-2-methylpropanoic acid (127 mg) in ethyl acetate (6 mL)at room temperature. The mixture was stirred under microwave irradiationat 130° C. for 30 minutes. The residue was purified by NH silica gelcolumn chromatography (methanol/ethyl acetate) to obtain the titlecompound (224 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.79 (6H, d, J=21.9 Hz), 2.62 (3H, s), 5.93(2H, s), 8.39 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

b)1-((5-(2-fluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(300 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2-fluoropropan-2-yl)-1,3,4-oxadiazole(110 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(10 mg), cesium carbonate (2 M in aqueous solution) (300 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by silica gel column chromatography (ethylacetate/hexane and methanol/ethyl acetate) to obtain a solid. Theobtained solid was crystallized from ethyl acetate/ethanol/heptane toobtain the title compound (47.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.78 (6H, d, J=21.9 Hz), 2.67 (3H, s), 3.95(3H, s), 5.97 (2H, s), 7.05 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz),8.18-8.27 (2H, m), 8.59 (1H, d, J=2.0 Hz).

Example 2791-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

A mixture of 2-fluoropropanoic acid (137 mg), Et3N (0.86 mL),propylphosphonic anhydride (50% in ethyl acetate solution) (2.2 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (350mg) and ethyl acetate (2.0 mL) was stirred under microwave irradiationat 135° C. for 30 minutes. The mixture was purified by NH silica gelcolumn chromatography (methanol/ethyl acetate) to obtain the titlecompound (188 mg).

MS: [M+H]⁺ 340.0.

b)1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole(186 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(500 mg)bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(30 mg), cesium carbonate (2 M in aqueous solution) (0.478 mL) and DME(2.5 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was purified by NH silica gel column chromatography(hexane/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (80 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.81 (3H, m), 2.67 (3H, s), 3.96 (3H,s), 5.85-6.13 (3H, m), 7.06 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.8 Hz),8.18-8.27 (2H, m), 8.59 (1H, d, J=2.1 Hz).

Example 2806-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiazol-4-ylmethyl)-1H-imidazo[4,5-b]pyridinea) N-(2-amino-5-bromopyridin-3-yl)-1,2,3-thiadiazole-4-carboxamide

A mixture of 5-bromopyridine-2,3-diamine (723 mg),1,2,3-thiadiazole-4-carboxylic acid (500 mg), HATU (2050 mg), Et3N (1.6mL) and DMF (8 mL) was stirred overnight at room temperature. Themixture was diluted with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith a saturated brine, then dried over magnesium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (754 mg). The title compound was used for the subsequentreaction without being further purified.

MS: [M+H]⁺ 299.9.

b) N3-((1,2,3-thiadiazol-4-yl)methyl)-5-bromopyridine-2,3-diamine

A BH3-THF complex (1M in THF solution) (10 mL) was added dropwise to asolution ofN-(2-amino-5-bromopyridin-3-yl)-1,2,3-thiadiazole-4-carboxamide (754 mg)in THF (10 mL) at room temperature. The mixture was stirred under anitrogen atmosphere at 60° C. for 2 hours. The reaction was stopped withwater at room temperature, and the mixture was then acidified with HCl(1 N in aqueous solution). The mixture was stirred at 60° C. for 30minutes. The mixture was neutralized with a saturated aqueous sodiumhydrogen carbonate solution at room temperature, and then extracted withethyl acetate. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/methanol) to obtain the title compound (135 mg).

MS: [M+H]⁺ 286.2.

c)4-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,2,3-thiadiazole

A mixture ofN3-((1,2,3-thiadiazol-4-yl)methyl)-5-bromopyridine-2,3-diamine (135 mg),acetic acid (0.045 mL), DMAP (8 mg), propylphosphonic anhydride (1.7 Min ethyl acetate solution) (0.505 mL), DIPEA (0.164 mL) and THF (1.5 mL)was stirred under microwave irradiation at 140° C. for 50 minutes. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (90 mg).

MS: [M+H]⁺ 309.9.

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiazol-4-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of4-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,2,3-thiadiazole(89 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(317 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(19 mg), cesium carbonate (2 M in aqueous solution) (0.30 mL) and DME(1.5 mL) was stirred under microwave irradiation at 100° C. for 1 hour.The mixture was purified by NH silica gel column chromatography(hexane/ethyl acetate), and the obtained solid was washed with IPE toobtain the title compound (32.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.75 (3H, s), 3.92 (3H, s), 6.01 (2H, s),7.05 (1H, d, J=2.8 Hz), 8.06 (1H, d, J=2.7 Hz), 8.22 (1H, s), 8.27 (1H,d, J=2.1 Hz), 8.55 (1H, d, J=2.0 Hz), 9.29 (1H, s).

Example 2816-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridinea)N′-(2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetyl)-3,3,3-trifluoropropanehydrazide

3,3,3-trifluoropropanoyl chloride (185 mg) was added to a solution of2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (300mg) in DMA (3 mL) at room temperature, and the mixture was stirred for 1hour. The reaction mixture was purified by NH silica gel columnchromatography (methanol/ethyl acetate) to obtain the title compound(370 mg).

MS: [M+H]⁺ 393.9.

b)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazole

pTsCl (470 mg) was added to a mixture of TEA (600 μl), trimethylaminemonohydrochloride (198 mg),N′-(2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetyl)-3,3,3-trifluoropropanehydrazide(369.9 mg) and acetonitrile (10 ml) at room temperature, and the mixturewas stirred overnight at room temperature. The reaction mixture waspurified by silica gel column chromatography (ethyl acetate/hexame andmethanol/ethyl acetate) to obtain the title compound (210 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 4.32 (2H, d, J=10.6 Hz), 5.95(2H, s), 8.37 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

c)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(2,2,2-trifluoroethyl)-1,3,4-oxadiazole(210 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(676 mg)bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (0.40 mL) and DME(4.0 mL) was stirred under microwave irradiation at 100° C. for 20minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate), andthe residue was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (49.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 3.95 (3H, s), 4.27-4.41 (2H,m), 5.98 (2H, s), 7.06 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.7 Hz), 8.21(1H, d, J=2.1 Hz), 8.23 (1H, s), 8.59 (1H, d, J=2.1 Hz).

Example 2826-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiazol-5-ylmethyl)-1H-imidazo[4,5-b]pyridinea) N-(2-amino-5-bromopyridin-3-yl)-1,2,3-thiadiazole-5-carboxamide

TEA (2.4 ml) was added to a mixture of 5-bromopyridine-2,3-diamine (1.08g), 1,2,3-thiadiazole-5-carboxylic acid (760 mg), HATU (2.93 g) and DMF(12 ml) at room temperature, and the mixture was stirred overnight. Thereaction mixture was diluted with a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layerwas washed with a saturated brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (0.900 g).

¹H NMR (300 MHz, DMSO-d₆) δ 6.36 (2H, s), 7.74 (1H, d, J=2.3 Hz), 7.98(1H, d, J=2.3 Hz), 9.49 (1H, s), 10.34 (1H, s).

b) N3-((1,2,3-thiadiazol-5-yl)methyl)-5-bromopyridine-2,3-diamine

A borane-THF complex (1.0 M) (10 ml) was added to a mixture ofN-(2-amino-5-bromopyridin-3-yl)-1,2,3-thiadiazole-5-carboxamide (0.90 g)and THF (10 ml) at 0° C., and the mixture was stirred overnight under anitrogen atmosphere at room temperature. To the reaction mixture wereadded methanol and hydrochloric acid (1N) at 0° C., and the mixture wasstirred at room temperature for 3 hours, and concentrated under reducedpressure. The residue was poured into an aqueous potassium carbonatesolution, and extracted with ethyl acetate. The organic layer was washedwith water and a saturated brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (0.330 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.83 (2H, d, J=5.9 Hz), 5.77 (2H, s), 5.96(1H, t, J=5.9 Hz), 6.76 (1H, d, J=2.1 Hz), 7.37 (1H, d, J=2.1 Hz), 8.92(1H, s).

c)5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,2,3-thiadiazole

A mixture of acetic acid (130 μl), DMAP (5.0 mg), DIEA (0.403 ml),N3-((1,2,3-thiadiazol-5-yl)methyl)-5-bromopyridine-2,3-diamine (330 mg),propylphosphonic anhydride (50% in ethyl acetate solution) (1.2 ml) andTHF (6.0 ml) was stirred under microwave irradiation at 150° C. for 1hour. The residue was purified by silica gel column chromatography(ethyl acetate/hexame and methanol/ethyl acetate) to obtain the titlecompound (220 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.61 (3H, s), 6.04 (2H, d, J=0.7 Hz), 8.44(2H, d, J=1.3 Hz), 8.90 (1H, s).

d)6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiazol-5-ylmethyl)-1H-imidazo[4,5-b]pyridine

A mixture of5-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-1,2,3-thiadiazole(210 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(820 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(40 mg), cesium carbonate (2 M in aqueous solution) (0.45 mL) and DME(4.0 mL) was stirred under microwave irradiation at 100° C. for 50minutes. The reaction mixture was purified by silica gel columnchromatography (ethyl acetate/hexane and methanol/ethyl acetate) and NHsilica gel column chromatography (methanol/ethyl acetate), and theresidue was crystallized from ethanol/ethyl acetate/heptane to obtainthe title compound (49.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.66 (3H, s), 3.85 (3H, s), 6.08 (2H, s),7.06 (1H, d, J=2.8 Hz), 8.07 (1H, d, J=2.7 Hz), 8.20-8.23 (2H, m), 8.58(1H, d, J=2.0 Hz), 8.92 (1H, s).

Example 2831-((5-(1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluorocyclopropyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (0.917 mL)was added to a suspension of triethylamine (0.307 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (125mg) and 1-fluorocyclopropanecarboxylic acid (50 mg) in ethyl acetate (2mL) at room temperature. The mixture was stirred under microwaveirradiation at 150° C. for 30 minutes. The residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (84 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.32-1.44 (2H, m), 1.61-1.77 (2H, m), 2.62(3H, s), 5.90 (2H, s), 8.38 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=2.2 Hz).

b)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluorocyclopropyl)-1,3,4-oxadiazole

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(245 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluorocyclopropyl)-1,3,4-oxadiazole(84 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(20 mg), cesium carbonate (2 M in aqueous solution) (220 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane and methanol/ethyl acetate) to obtain a solid. Theobtained solid was washed with ethyl acetate/hexane to obtain the titlecompound (32.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.45 (2H, m), 1.61-1.76 (2H, m), 2.66(3H, s), 3.97 (3H, s), 5.93 (2H, s), 7.06 (1H, d, J=2.7 Hz), 8.07 (1H,d, J=2.7 Hz), 8.20-8.27 (2H, m), 8.59 (1H, d, J=2.1 Hz).

Example 2841-((5-(1-fluorocyclobutyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluorocyclobutyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (0.917 mL)was added to a suspension of triethylamine (0.307 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (125mg) and 1-fluorocyclobutanecarboxylic acid (50 mg) in ethyl acetate (2mL) at room temperature. The mixture was stirred under microwaveirradiation at 150° C. for 30 minutes. The residue was purified by NHsilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (101 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-1.76 (1H, m), 1.86-2.04 (1H, m),2.57-2.77 (7H, m), 5.93 (2H, s), 8.39 (1H, d, J=2.2 Hz), 8.45 (1H, d,J=2.2 Hz).

b)1-((5-(1-fluorocyclobutyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(283 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluorocyclobutyl)-1,3,4-oxadiazole(101 mg), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(10 mg), cesium carbonate (2 M in aqueous solution) (250 μL) and DME (4mL) was stirred under microwave irradiation at 100° C. for 40 minutes.The residue was purified by NH silica gel column chromatography (ethylacetate/hexane and methanol/ethyl acetate) to obtain a solid. Theobtained solid was washed with ethyl acetate/hexane to obtain the titlecompound (42.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.55-1.76 (1H, m), 1.84-2.05 (1H, m),2.58-2.76 (7H, m), 3.95 (3H, s), 5.96 (2H, s), 7.05 (1H, d, J=2.7 Hz),8.07 (1H, d, J=2.7 Hz), 8.19-8.27 (2H, m), 8.59 (1H, d, J=2.0 Hz).

Example 2861-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine(Optical Isomer) a)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

Propylphosphonic anhydride (50% in ethyl acetate solution) (6.0 mL) wasadded to a mixture of 2-fluoropropionic acid (0.58 mL), DIEA (3.0 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (1.33g) and ethyl acetate (40 ml) at room temperature, and the resultingmixture was stirred at 50° C. for 1 hour. The mixture was stirred undermicrowave irradiation at 140° C. for 2.5 hours. Insolubles were removedby filtration through a filter, and the filtrate was concentrated. Theresidue was purified by NH silica gel column chromatography(methanol/ethyl acetate), and washed with IPE to obtain the titlecompound (0.644 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.64-1.77 (3H, m), 2.62 (3H, s), 5.86-6.12(3H, m), 8.38 (1H, d, J=2.2 Hz), 8.45 (1H, d, J=2.2 Hz).

b)1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole(186 mg),4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(500 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(30 mg), cesium carbonate (2 M in aqueous solution) (0.478 ml) and DME(2.5 ml) was stirred under microwave irradiation at 100° C. for 1 hour.The reaction mixture was purified by NH silica gel column chromatography(ethyl acetate/hexane), and the residue was washed with IPE to obtainthe title compound (80 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.56-1.86 (3H, m), 2.67 (3H, s), 3.96 (3H,s), 5.98 (3H, s), 7.06 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=2.8 Hz),8.19-8.35 (2H, m), 8.59 (1H, d, J=2.1 Hz).

c)1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine(Optical Isomer)

A racemate of1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine(66.5 mg) was fractionated by SFC (column: CHIRALPAK ASH (LA005) 20×250mm, 5 μm, mobile phase: CO₂/methanol=800/200), and a compound with asmaller retention time was crystallized with ethanol/ethylacetate/heptane to obtain the title compound (12.8 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.89 (3H, m), 2.84 (3H, s), 4.06 (3H, s),5.57 (2H, s), 5.61-5.87 (1H, m), 6.87 (1H, d, J=2.8 Hz), 7.77 (1H, d,J=2.7 Hz), 7.95 (1H, d, J=2.0 Hz), 8.07 (1H, s), 8.75 (1H, d, J=2.0 Hz).

Another method for producing1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinemonohydrate (identical to the title compound in Example 286) is shownbelow.

a) (4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)boronic acid

To a solution of 5-bromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (60 g)and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (243 mL) in THF(3000 mL) was added dropwise n-butyllithium (1.6 M in hexane solution)(411 mL) under an argon atmosphere at −78° C. to −60° C. over 45minutes. The mixture was stirred at −70° C. to −60° C. for 30 minutesunder an argon atmosphere. To the reaction mixture were added water (140mL) and hydrochloric acid (2 N in aqueous solution) (600 mL), and themixture was warmed to room temperature. The aqueous layer was extractedwith isopropyl acetate. The organic layer was inversely extracted with a2N aqueous sodium hydroxide solution (700 mL) and water (300 mL). Theaqueous layer was acidified with hydrochloric acid (2N in aqueoussolution) (7100 mL) at 10° C., and the suspension was filtered. Theobtained residue was washed with water to obtain the title compound(40.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ 4.13 (3H, s), 7.07 (1H, d, J=2.3 Hz), 7.68(2H, s), 7.94 (1H, d, J=2.6 Hz), 8.24 (1H, s).

b) (R)-2-fluoropropanoic acid

(R)-Ethyl 2-fluoropropanoate (95 g) was suspended in 10% sulfuric acid(950 mL), and heated and refluxed for 3 hours. After cooled, sodiumchloride was added to saturate the aqueous layer, and the aqueous layerwas extracted with t-butyl methyl ether (900 mL×4). The obtained organiclayer was dried over magnesium sulfate, and concentrated under reducedpressure to obtain the title compound (124 g, containing t-butyl methylether).

¹H NMR (300 MHz, DMSO-d₆) δ 1.35-1.56 (3H, m), 4.91-5.21 (1H, m), 13.19(1H, brs).

c) (S)-2-amino-3-phenylpropane-1-ol (R)-2-fluoropropanoate

To a solution of (S)-2-amino-3-phenylpropan-1-ol (119 g) in ethanol (360mL) and acetonitrile (1090 mL) was added dropwise a solution of(R)-2-fluoropropanoic acid (72.7 g) in acetonitrile (1090 mL) at 65° C.to 70° C. The mixture was stirred at 60° C. for 1 hour, and furtherstirred at room temperature for 1 hour. Precipitated crystals werecollected by filtration, and washed with acetonitrile (500 mL) to obtainwhite crystals (170 g). The obtained crystals (140 g) were dissolved inethanol (700 mL) at 60° C., and to the solution was added acetonitrile(4200 mL) at 58° C. to 65° C. The mixture was stirred at 60° C. for 1hour. The mixture was cooled to room temperature, and then stirredovernight at room temperature. The obtained solid was collected byfiltration, and washed with acetonitrile to obtain the title compound(109 g).

d)(R)-2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole

(S)-2-Amino-3-phenylpropan-1-ol (R)-2-fluoropropanoate (109 g) wasdissolved in hydrochloric acid (1N in aqueous solution) (1500 mL) and asaturated brine (1500 mL), and the solution was extracted with t-butylmethyl ether (1000 mL×4). The organic layer was dried over magnesiumsulfate, and concentrated under reduced pressure to obtain a colorlessoil. Propylphosphonic anhydride (50% in ethyl acetate solution) (419 mL)was added to a suspension of the obtained oil,2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (100g), DIPEA (246 mL) and butyl acetate (3000 mL) at room temperature. Themixture was stirred at 50° C. for 30 minutes, propylphosphonic anhydride(50% in ethyl acetate solution) (210 mL) was added to the mixture, andthe resulting mixture was heated and refluxed for 3 hours. The mixturewas cooled, a saturated aqueous sodium hydrogen carbonate solution (3000mL) was then added to the mixture, and insolubles were removed. Theliquid layer was extracted twice with ethyl acetate (1500 mL×2), and theorganic layer was washed with water and a saturated brine. The organiclayer was purified with NH silica gel (ethyl acetate). The residue wasconcentrated under reduced pressure, and the obtained solid was washedwith IPE (3000 mL) to obtain the title compound (57.8 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.62-1.79 (3H, m), 2.62 (3H, s), 5.83-6.14(3H, m), 8.38 (1H, d, J=1.9 Hz), 8.45 (1H, d, J=1.9 Hz).

e)1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinemonohydrate

A mixture of (4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)boronic acid(79 g),(R)-2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(1-fluoroethyl)-1,3,4-oxadiazole(100 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(2.00 g), cesium carbonate (2 M in aqueous solution) (295 mL) and DME(2000 mL) was stirred at 80° C. for 1 hour. The mixture was cooled to50° C., and then diluted with THF (1000 mL). The mixture was poured intoan aqueous sodium hydrogen carbonate solution (1600 mL), and extractedwith ethyl acetate (1000 mL×3). The organic layer was washed with a 5%aqueous ammonia solution (1600 mL×2) and a saturated brine (1600 mL),dried over magnesium sulfate, and concentrated under reduced pressure toobtain a yellow solid. NH silica gel (2400 g) was added to a solution ofthe obtained solid in THF (8000 mL) and water (200 mL), and the mixturewas stirred at room temperature for 3.5 hours. Insolubles were removed,and washed with THF (15 L). The obtained solution was concentrated underreduced pressure to obtain a yellow solid. The obtained solid was washedwith t-butyl methyl ether to obtain pale yellow crystals (98 g).

A mixture of the obtained crystals (115 g), activated carbon (Ecosorb)(33 g), ethanol/water=9/1 (2200 mL) and water (1100 mL) was stirred at55° C. for 1 hour. Insolubles were removed, and washed with ethanol (550mL). The obtained solution was diluted with water (1600 mL) at 55° C.,and stirred overnight at room temperature. The mixture was cooled to 5°C., and then stirred for 3 hours. The obtained solid was collected byfiltration, and washed with ethanol/water=1/1 (1000 mL) to obtain thetitle compound (88 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.83 (3H, m), 2.67 (3H, s), 3.96 (3H,s), 5.83-6.19 (3H, m), 7.06 (1H, d, J=2.5 Hz), 8.06 (1H, d, J=2.5 Hz),8.17-8.30 (2H, m), 8.59 (1H, d, J=2.0 Hz).

Example 287 1-((5-((1S)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine(Optical Isomer)

A racemate of1-((5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine(66.5 mg) was fractionated by SFC (column: CHIRALPAK ASH (LA005) 20×50mm, 5 μm, mobile phase: CO₂/methanol=800/200), and a compound with alarger retention time was crystallized with ethanol/ethylacetate/heptane to obtain the title compound (15.7 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.87 (3H, m), 2.84 (3H, s), 4.06 (3H, s),5.57 (2H, s), 5.62-5.87 (1H, m), 6.87 (1H, d, J=2.8 Hz), 7.77 (1H, d,J=2.7 Hz), 7.94 (1H, d, J=1.9 Hz), 8.07 (1H, s), 8.75 (1H, d, J=1.9 Hz).

Example 2881-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine

n-butyllithium (1.6 M in hexane solution) (4.5 mL) was added dropwise toa solution of 5-bromo-4-methoxypyrrolo[1,2-b]pyridazine (1.20 g) in THF(30 mL) under a nitrogen atmosphere at −78° C. The mixture was stirredat −78° C. for 20 minutes, and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 mL) was thenadded. The mixture was warmed to room temperature, and stirred for 30minutes. The reaction mixture was poured into water, and extracted withethyl acetate. The organic layer was washed with a saturated brine, thendried over magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (0.707 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (12H, s), 3.94 (3H, s), 6.30 (1H, d,J=5.5 Hz), 6.87 (1H, d, J=2.5 Hz), 7.75 (1H, d, J=2.6 Hz), 8.11 (1H, d,J=5.5 Hz).

b)1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-b]pyridazine(91 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(difluoromethyl)-1,3,4-oxadiazole(120 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(11 mg), cesium carbonate (2 M in aqueous solution) (0.350 mL) and DME(3 mL) was stirred under microwave irradiation at 100° C. for 40minutes. The residue was purified by silica gel column chromatography(ethyl acetate/hexane and methanol/ethyl acetate) to obtain a solid. Theobtained solid was crystallized from ethanol/ethyl acetate/heptane toobtain the title compound (57 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.65 (3H, s), 3.81 (3H, s), 6.00 (2H, s),6.27 (1H, d, J=5.6 Hz), 6.91 (1H, d, J=2.8 Hz), 7.21-7.70 (1H, m), 7.90(1H, d, J=2.8 Hz), 8.04-8.13 (2H, m), 8.50 (1H, d, J=2.0 Hz).

Example 2891-((5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridinea)2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(difluoromethyl)-1,3,4-thiadiazole

A mixture of triethylamine (4.00 mL), difluoroacetic acid (0.50 mL),propylphosphonic anhydride (50% in ethyl acetate solution) (10.00 mL),2-(6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)acetohydrazide (1.72g), diphosphorus pentasulfide (3.33 g) and ethyl acetate (50 mL) washeated overnight at 80° C. The mixture was purified by NH silica gelcolumn chromatography (ethyl acetate). The obtained residue was purifiedby NH silica gel column chromatography (ethyl acetate/hexane) to obtainthe title compound (0.711 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.63 (3H, s), 6.15 (2H, s), 7.33-7.78 (1H,m), 8.41-8.50 (2H, m).

b)1-((5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

A mixture of4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazine(430 mg),2-((6-bromo-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-5-(difluoromethyl)-1,3,4-thiadiazole(150 mg),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(25 mg), cesium carbonate (2 M in aqueous solution) (500 μL) and DME (10mL) was stirred under microwave irradiation at 100° C. for 2 hours. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane and methanol/ethyl acetate) to obtain a solid. Theobtained solid was washed with ethanol/ethyl acetate/heptane to obtainthe title compound (48.0 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.68 (3H, s), 3.90 (3H, s), 6.18 (2H, s),7.05 (1H, d, J=2.7 Hz), 7.34-7.78 (1H, m), 8.06 (1H, d, J=2.7 Hz), 8.22(1H, s), 8.24 (1H, d, J=2.0 Hz), 8.58 (1H, d, J=2.0 Hz).

The compounds of Examples 2 to 6, 8 and 9, 11, 14 to 16, 18 and 19, 25and 26, 29 and 30, 36 and 37, 40 to 43, 45 to 47, 49 to 67, 69 to 78, 80and 81, 83 to 95, 97, 99 to 101, 103 and 104, 106 to 109, 111 to 133,135 to 155, 157, 163 to 174, 177 and 178, 180 to 185, 187 to 190, 192,194 to 198, 200 to 202, 216 to 219, 221 to 228, 232 to 236, 238 to 241,244 to 249, 251, 254 to 266, 270 to 272, 275, 278, 285 and 290 in thetable below were produced in accordance with the methods shown in theabove-described examples, or similar methods. The example compounds areshown in the table below. MS in the table indicates a measured value.

TABLE 1 Example IUPAC NAME CHEMICAL STRUCTURE Salt MS 12-(azetidin-1-yl)-1-(3,5- difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

448.2 2 1-(3,4-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-N-methyl-1H- imidazo[4,5-b]pyridin-2-amine

422.2 3 1-(3,4-difluorobenzyl)-2-ethoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

437.2 4 2-(1,1-difluoroethyl)-1-(3- fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

439.2 5 1-(3,4-difluorobenzyl)-N-methyl-6-(5H-pyrrolo[3,2-d]pyrimidin-5- yl)-1H-imidazo[4,5-b]pyridin-2- amine

392.2 6 2-(azetidin-1-yl)-1-(2,5- difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

448.2 7 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 8 1-(3,5-difluorobenzyl)-N-(2,2- difluoroethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridin-2-amine

472.1 9 2-(3,3-difluoroazetidin-1-yl)-1- (3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

484.2 10 2-ethoxy-1-(3-fluorobenzyl)-6- (4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

419.1 11 2-ethoxy-1-((5-fluoropyridin-3- yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

420.2 12 1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

389.2 13 (1-(3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)methanol

405.2 14 3-(1-(3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)propanenitrile

428.3 15 1-(4-(difluoromethoxy)benzyl)-6- (4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

437.2 16 1-(3-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine

455.2 17 1-(3,4-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 18 1-(1-(3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)azetidin-3-ol

446.3 19 2-(3-fluoroazetidin-1-yl)-1-(3- fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

448.2 20 1-(2,3-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 21 1-benzyl-6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

371.2 22 1-(4-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

389.1 23 1-(2,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 24 1-(3-fluorobenzyl)-2- (methoxymethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 1H-imidazo[4,5-b]pyridine

419.2 25 6-(4-chloro-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1-(3-fluorobenzyl)-2-methyl-1H- imidazo[4,5-b]pyridine

393.1 26 2-((1-(3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine-2-yl)oxy)ethanol

435.2 27 5-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-N- methyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine

388.2 28 1-(2-fluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

389.2 29 1-(1-(3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)ethanol

419.3 30 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-(3-nitrobenzyl)-1H-imidazo[4,5- b]pyridine

416.2 31 1-(2,4-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 32 1-(3-chlorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

405.1 33 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-(3-(trifluoromethoxy)benzyl)-1H- imidazo[4,5-b]pyridine

455.2 34 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-(3-(trifluoromethyl)benzyl)-1H- imidazo[4,5-b]pyridine

439.1 35 1-(2,6-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

407.1 36 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-(2,3,4-trifluorobenzyl)-1H- imidazo[4,5-b]pyridine

425.1 37 1-(2,3-difluorobenzyl)-2-ethoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

437.2 38 1-(3,5-difluorobenzyl)-2-methoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

423.1 39 1-(3-fluorobenzyl)-2-methoxy-6- (4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

405.1 40 2-((1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)amino)ethanol

452.1 41 1-(3,4-difluorobenzyl)-2-methoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

423.1 42 1-(3,4-difluorobenzyl)-N-(2- methoxyethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridin-2-amine

466.2 43 1-((1-(3,4-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)pyrrolidin-3-ol

478.2 44 1-(3-(difluoromethoxy)benzyl)-6- (4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

437.2 45 tert-butyl (3-((6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenyl)carbamate

486.1 46 3-((6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)aniline

386.1 47 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-(pyridin-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

372.2 48 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-amine

408.2 49 1-((1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)amino)-2-methylpropan-2-ol

480.2 50 1-(3,5-difluorobenzyl)-6-(4- (difluoromethoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-N-methyl-1H- imidazo[4,5-b]pyridin-2-amine

458.1 51 1-((5-fluoropyridin-3-yl)methyl)- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.2 52 1-((2-fluoropyridin-4-yl)methyl)- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.2 53 1-(3-chloro-4-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

423.1 54 1-(4-chloro-3-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

423.1 55 methyl 3-((6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin- 1-yl)methyl)benzoate

429.2 56 3-((6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)benzoic acid

415.2 57 3-((6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)-N-methylaniline

400.2 58 3-((6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1- yl)methyl)-N-methylbenzamide

428.2 59 2-(3-((6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin- 1-yl)methyl)phenyl)propan-2-ol

429.2 60 2-methoxy-6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-1-(2,4,5-trifluorobenzyl)-1H- imidazo[4,5-b]pyridine

441.1 61 1-benzyl-2-methoxy-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

387.2 62 1-(2,5-difluorobenzyl)-2-methoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-indazo[4,5- b]pyridine

423.1 63 1-(2,3-difluorobenzyl)-2-methoxy- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-indazo[4,5- b]pyridine

423.1 64 2-methoxy-6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-1-(2,3,4-trifluorobenzyl)-1H- imidazo[4,5-b]pyridine

441.1 65 2-methoxy-6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-1-(2,3,6-trifluorobenzyl)-1H- imidazo[4,5-b]pyridine

441.1 66 (3-((6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin- 1-yl)methyl)phenyl)methanol

401.2 67 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-(1-methyl- 1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridine

473.2 68 1-(3-fluoro-5- (trifluoromethyl)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

457.1 69 1-(3,5-dichlorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

439.1 70 1-(3-fluoro-5-nitrobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

434.1 71 3-fluoro-5-((6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin- 1-yl)methyl)aniline

404.2 72 1-(3,5-difluorobenzyl)-2-(1- (difluoromethyl)-1H-pyrazol-4-yl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

507.2 73 2-methoxy-6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-1-(2,3,5-trifluorobenzyl)-1H- imidazo[4,5-b]pyridine

441.1 74 2-fluoro-4-((6-(4-methoxy-5H- pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridin- 1-yl)methyl)benzonitrile

414.1 75 1-(5-fluoro-2-methoxybenzyl)-6- (4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

419.1 76 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2- (tetrahydrofuran-3-ylmethoxy)-1H-imidazo[4,5-b]pyridine

493.2 77 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-((1-methyl- 1H-pyrazol-4-yl)methoxy)-1H-imidazo[4,5-b]pyridine

503.1 78 1-(3,5-difluorobenzyl)-2- (difluoromethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 1H-imidazo[4,5-b]pyridine

441.1 79 1-(3-chloro-5-fluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

423.1 80 1-(3-fluoro-4- (trifluoromethyl)benzyl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

457.1 81 2-((3,3-difluoroazetidin-1- yl)methyl)-1-(3,5-difluorobenzyl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1H-imidazo[4,5-b]pyridine

498.1 82 (1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)methanol

423.1 83 1-((6-methoxypyridin-2- yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

402.2 84 1-((6-chloropyridin-2-yl)methyl)- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

406.1 85 (1-(2,3-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)methanol

423.1 86 1-(3,5-difluorobenzyl)-6-(4- (fluoromethoxy)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

425.1 87 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-(1,3-oxazol-5- yl)-1H-imidazo[4,5-b]pyridine

460.2 88 2-((1-((3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)methoxy)ethanol

467.1 89 1-(3,5-difluorobenzyl)-6-(4- methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-((2,2,2- trifluoroethoxy)methyl)-1H-imidazo[4,5-b]pyridine

505.1 90 1-(3,5-difluorobenzyl)-2-((2,2- difluoroethoxy)methyl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

487.1 91 1-(2-furylmethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

361.1 92 1-(3-fluorobenzyl)-2-(3- methoxyazetidin-1-yl)-6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-1H-imidazo[4,5- b]pyridine

460.2 93 1-(3-furylmethyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)- 2-methyl-1H-imidazo[4,5- b]pyridine

361.1 94 6-(4-methoxy-5H-pyrrolo[3,2- d]pyrimidin-5-yl)-2-methyl-1-((6-(trifluoromethyl)pyridin-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

440.1 95 2-(2-fluoro-4-((6-(4-methoxy- 5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H-imidazo[4,5- b]pyridin-1- yl)methyl)phenoxy)ethanol

449.1 96 1-((6-fluoropyridin-2-yl)methyl)- 6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.1 97 1-((2-chloro-6-methylpyridin-4- yl)methyl)-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

418.0 98 1-((6-fluoropyridin-2-yl)methyl)- 2-methoxy-6-(4-methoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-1H- imidazo[4,5-b]pyridine

406.2 99 1-(3,4-difluorobenzyl)-N-methyl-6-(1H-pyrrolo[3,2-b]pyridin-1-yl)- 1H-imidazo[4,5-b]pyridin-2-amine

391.2 100 1-(3,5-difluorobenzyl)-6-(7- methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-N-methyl-1H- imidazo[4,5-b]pyridin-2-amine

421.2 101 1-(3,5-difluorobenzyl)-2-ethoxy- 6-(7-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-1H-imidazo[4,5- b]pyridine

436.2 102 1-(3-fluorobenzyl)-6-(7-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

388.2 103 1-(3,4-difluorobenzyl)-N-methyl-6-(1H-pyrazolo[4,3-b]pyridin-1- yl)-1H-imidazo[4,5-b]pyridin-2- amine

392.2 104 1-(3,4-difluorobenzyl)-6-(7- methoxy-1H-pyrazolo[4,3-b]pyridin-1-yl)-N-methyl-1H- imidazo[4,5-b]pyridin-2-amine

422.2 105 1-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-7- methoxy-1H-pyrazolo[4,3- b]pyridine

389.2 106 1-(3,5-difluorobenzyl)-6-(3- methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-N-methyl-1H- imidazo[4,5-b]pyridin-2-amine

422.1 107 1-(3,5-difluorobenzyl)-N-methyl-6-(5H-pyrrolo[2,3-b]pyrazin-5- yl)-1H-imidazo[4,5-b]pyridin-2- amine

392.1 108 (1-(3-fluorobenzyl)-6-(3- methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)-methanol

405.1 109 (1-(3,5-difluorobenzyl)-6-(3- methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)-methanol

423.1 110 1-(3-fluorobenzyl)-6-(3-methoxy-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2- methyl-1H-imidazo[4,3-b]pyridine

389.2 111 2-(5-(1-(3-fluorobenzyl)-2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)propan-2-ol

417.1 112 1-(3-fluorobenzyl)-2-methyl-6-(5H-pyrrolo[2,3-b]pyrazin-5-yl)- 1H-imidazo[4,5-b]pyridine

359.1 113 1-(5-(1-(3-fluorobenzyl)-2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)ethanone

401.2 114 6-(3-chloro-5H-pyrrolo[2,3- b]pyrazin-5-yl)-1-(3-fluorobenzyl)-2-methyl-1H- imidazo[4,5-b]pyridine

393.1 115 1-(3-fluorobenzyl)-2-methyl-6- (3-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)- 1H-imidazo[4,5-b]pyridine

439.2 116 5-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)- 5H-pyrrolo[2,3-b]pyrazin-3-ol

375.2 117 1-(3-fluorobenzyl)-2-methyl-6- (3-methyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridine

373.2 118 N-(2,2-difluoroethyl)-5-(1-(3- fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5H- pyrrolo[2,3-b]pyrazin-3-amine

438.2 119 2-(5-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin- 6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)propan-2-ol

435.2 120 1-(5-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin- 6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)ethanol

421.1 121 5-(1-(3-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)- 5H-pyrrolo[2,3-b]pyrazine-3-carbonitrile

384.1 122 2-(5-(1-(3,5-difluorobenzyl)-2- methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)propan-2-ol

451.2 123 1-(3,5-difluorobenzyl)-N-(2,2-difluoroethyl)-6-(5H-pyrrolo[2,3- b]pyrazin-5-yl)-1H-imidazo[4,5-b]pyridin-2-amine

442.1 124 1-(3,5-difluorobenzyl)-2-methoxy-6-(5H-pyrrolo[2,3-b]pyrazin-5- yl)-1H-imidazo[4,5-b]pyridine

393.1 125 1-(3,5-difluorobenzyl)-6-(5H- pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5-b]pyridin-2-amine

378.2 126 6-(3-(1-difluoromethyl)-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1-(3- fluorobenzyl)-2-methyl-1H- imidazo[4,5-b]pyridine

475.2 127 1-(3,5-difluorobenzyl)-2-methyl-6-(5H-pyrrolo[2,3-b]pyrazin-5- yl)-1H-imidazo[4,5-b]pyridine

377.2 128 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)-5H-pyrrolo[2,3-b]pyrazin- 5-yl)-1H-imidazo[4,5-b]pyridine

473.1 129 1-(3,5-difluorobenzyl)-6-(3-(3- fluoroazetidin-1-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

450.1 130 1-(5-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin- 6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)pyrrolidin-2-one

460.3 131 1-(3,5-difluorobenzyl)-6-(3-(3,6- dihydro-2H-pyran-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

459.2 132 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-(1H-pyrazol-1-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H- imidazo[4,5-b]pyridine

443.2 133 1-(3,5-difluorobenzyl)-2-methyl-6-(3-tetrahydro-2H-pyran-4-yl)- 5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5-b]pyridine

461.2 134 1-(5-(1-(3,5-difluorobenzyl)-2- methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)ethanol

437.2 135 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-(pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H- imidazo[4,5-b]pyridine

454.2 136 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H- imidazo[4,5-b]pyridine

454.2 137 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-(pyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H- imidazo[4,5-b]pyridine

454.2 138 4-(5-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin- 6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)benzonitrile

478.2 139 3-(5-(1-(3,5-difluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin- 6-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)benzonitrile

478.2 140 1-(3,5-difluorobenzyl)-2-methyl-6-(3-(1-(2-(morpholin-4-yl)ethyl)- 1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridine

556.3 141 1-(3,5-difluorobenzyl)-2-methyl-6-(3-(1-(pyridin-2-ylmethyl)-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridine

534.2 142 1-(3,5-difluorobenzyl)-2-methyl-6-(3-(1-(pyridin-3-ylmethyl)-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridine

534.2 143 1-(3,5-difluorobenzyl)-2-methyl-6-(3-(1-methyl-1H-pyrazol-3-yl)- 5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5-b]pyridine

457.2 144 1-(3,5-difluorobenzyl)-6-(3-(1,3-dimethyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

471.2 145 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5-b]pyridine

525.2 146 1-(3,5-difluorobenzyl)-6-(3-(3,5-dimethyl-1,2-oxazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

472.2 147 1-(3,5-difluorobenzyl)-2-methyl- 6-(3-vinyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)-1H-imidazo[4,5- b]pyridine

403.1 148 1-(3,5-difluorobenzyl)-6-(3-((1Z)-3-methoxyprop-1-en-1-yl)-5H- pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

447.2 149 (5-(1-(3,5-difluorobenzyl)-2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)methyl pivalate

491.2 150 1-(3,5-difluorobenzyl)-6-(3-(1- methoxyethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

435.1 151 (5-(1-(3,5-difluorobenzyl)-2- methyl-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3-b]pyrazin-3- yl)methanol

407.1 152 1-(3,5-difluorobenzyl)-6-(3- (methoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

421.2 153 1-(3,5-difluorobenzyl)-6-(3- (difluoromethyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

427.1 154 1-(3,5-difluorobenzyl)-6-(3- ethynyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2-methyl-1H-imidazo[4,5- b]pyridine

401.1 155 1-(3,5-difluorobenzyl)-6-(3-((2- methoxyethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

465.1 157 1-(3,5-difluorobenzyl)-6-(3-(3- methoxyoxetan-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)-2- methyl-1H-imidazo[4,5-b]pyridine

463.1 159 (R)-1-(5-(1-(3,5-difluorobenzyl)- 2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)ethanol

437.2 159 (S)-1-(5-(1-(3,5-difluorobenzyl)- 2-methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)ethanol

437.2 160 1-(5-(1-(3-fluorobenzyl)-2- methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)ethanol

419.2 161 1-(5-(1-(3-fluorobenzyl)-2- methoxy-1H-imidazo[4,5-b]pyridin-6-yl)-5H-pyrrolo[2,3- b]pyrazin-3-yl)ethanol

419.1 162 1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1H-imidazo[4,5- b]pyridine

406.1 163 1-((2-fluoropyridin-4-yl)methyl)- 6-(4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

389.2 164 6-(4-methoxypyrrolo[1,2- b]pyridazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-oxadiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.1 165 1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[1,2-b]pyridazin-5-yl)-2-(1-methyl-1H-pyrazol-4-yl)- 1H-imidazo[4,5-b]pyridine

472.2 166 6-(4-methoxypyrrolo[1,2- b]pyridazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-5-yl)methyl)- 1H-imidazo[4,5-b]pyridine

374.2 167 (1-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol

422.1 168 (1S)-1-(1-(3,5-difluorobenzyl)-6- (4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)ethanol

436.2 169 1-(1-(3,5-difluorobenzyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-1H-imidazo[4,5-b]pyridin-2-yl)azetidin-3-ol

463.2 170 (1R)-1-(1-(3,5-difluorobenzyl)-6- (4-methoxypyrrolo[1,2-b]pyridazin-5-yl)-1H-imidazo[4,5- b]pyridin-2-yl)ethanol

436.1 171 1-((2-fluoropyridin-4-yl)methyl)- 2-(methoxymethyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-1H-imidazo[4,5-b]pyridine

417.1 172 2-cyclopropyl-1-((2-fluoropyridin- 4-yl)methyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-1H-imidazo[4,5-b]pyridine

413.1 173 2-(azetidin-1-yl)-1-((2- fluoropyridin-4-yl)methyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-1H-imidazo[4,5-b]pyridine

430.2 174 1-(3,5-difluorobenzyl)-2-methyl-6-(pyrrolo[1,2-b]pyridazin-5-yl)- 1H-imidazo[4,5-b]pyridine

376.1 175 1-(3-fluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

389.2 176 (1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)methanol

423.1 177 1-(3,5-difluorobenzyl)-2-methyl-6-(pyrrolo[2,1-f][1,2,4]triazin-5- yl)-1H-imidazo[4,5-b]pyridine

377.2 178 1-((2-fluoropyridin-4-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.2 179 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

375.2 180 1-((2-fluoropyridin-4-yl)methyl)- 2-(methoxymethyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridine

420.2 181 1-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2-yl)ethanol

437.2 182 2-(azetidin-1-yl)-1-((2- fluoropyridin-4-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridine

431.2 183 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-(trifluoromethyl)pyridin-4- yl)methyl)-1H-imidazo[4,5- b]pyridine

440.1 184 1-((2-methoxypyridin-4- yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

402.1 185 1-((2-chloropyridin-4-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

406.1 186 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-oxadiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

377.2 187 2-cyclopropyl-1-((2-fluoropyridin- 4-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridine

416.1 188 2-(3,3-difluorocyclobutyl)-1-((2-fluoropyridin-4-yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridine

466.2 189 1-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2-yl)ethanol

437.1 190 1-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2-yl)ethanol

437.1 191 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-thiazol-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

378.2 192 3-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)propanenitrile

446.1 193 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,3,4-oxadiazol-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

377.2 194 1-((6-fluoropyridin-2-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.1 195 1-((6-chloropyridin-2-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

406.1 196 1-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)azetidin-3-ol

464.2 197 2-ethoxy-1-((2-fluoropyridin-4- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridine

420.2 198 (1-(3,5-difluorobenzyl)-6-(4-ethoxypyrrolo[2,1-f][1,2,4]triazin- 5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol

437.1 199 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxazol-4- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 200 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methylpyridin-4-yl)methyl)- 1H-imidazo[4,5-b]pyridine

386.1 201 1-((2-chloro-6-methylpyridin-4- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

420.1 202 (1-(3-fluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)methanol

405.1 203 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-3- yl)methyl)-1H-imidazo[4,5- b]pyridine

375.2 204 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-4- yl)methyl)-1H-imidazo[4,5- b]pyridine

392.1 205 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(1,3-oxazol-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

362.2 206 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,3-triazol-4- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 207 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-oxazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 208 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrazin-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

373.2 209 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(pyrimidin-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

373.2 210 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-4-ylmethyl)-1H- imidazo[4,5-b]pyridine

372.2 211 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-3-ylmethyl)-1H- imidazo[4,5-b]pyridine

372.2 212 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2-oxazol-3- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 213 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methyl-1,3-thiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

392.1 214 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,2,4-oxadiazol-3- yl)methyl)-1H-imidazo[4,5- b]pyridine

377.2 215 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2-oxazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 216 1-((3-cyclopropyl-1,2,4-oxadiazol- 5-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

401.1 217 1-((3-(difluoromethyl)-1,2,4- oxadiazol-5-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

411.1 218 1-((1,3-dimethyl-1H-pyrazol-5- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

389.2 219 1-((2-fluoropyridin-3-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.2 220 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,3,4-thiadiazol-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

393.2 221 1-((4-chloropyridin-2-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

406.1 222 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2-thiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

392.1 223 2-(1-(3,5-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2-yl)ethanol

437.2 224 1-((3,5-dimethyl-1,2-oxazol-4- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

390.2 225 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((4-methyl-1,3-thiazol-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

391.9 226 1-((3-ethyl-1,2,4-oxadiazol-5- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

389.0 227 1-((5-fluoropyridin-3-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

390.2 228 (1-(3,4-difluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)methanol

423.1 229 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-thiadiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

393.2 230 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-pyrazol-4- yl)methyl)-1H-imidazo[4,5- b]pyridine

375.2 231 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-1H-1,2,4-triazol-3- yl)methyl)-1H-imidazo[4,5- b]pyridine

376.2 232 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-methyl-1,3-thiazol-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

392.1 233 3-((6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-4-methyl-1,2,4- oxadiazol-5(4H)-one

393.2 234 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((3-(trifluoromethyl)-1,2,4- oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

429.0 235 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((2-methylpyrimidin-4-yl)methyl)- 1H-imidazo[4,5-b]pyridine

387.2 236 1-(2-furylmethyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

361.2 237 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(pyridin-2-ylmethyl)-1H- imidazo[4,5-b]pyridine

372.2 238 1-((1,5-dimethyl-1H-pyrazol-3- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

389.2 239 2-(methoxymethyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1-((3-methyl- 1,2,4-oxadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

405.0 240 1-((3-methoxy-1-methyl-1H- pyrazol-5-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

405.2 241 2,2,2-trifluoro-1-(1-((2- fluoropyridin-4-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)ethanol

474.1 242 1-((5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

413.2 243 1-((5-(1,1-difluoroethyl)-1,2,4- oxadiazol-3-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

425.0 244 1-((4,6-dimethylpyrimidin)-2- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

401.2 245 1-((1-(difluoromethyl)-1H- pyrazol-3-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

411.2 246 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((1-methyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine

443.2 247 1-((1-(difluoromethyl)-1H- pyrazol-5-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

411.2 248 1-((6-chloropyrazin-2-yl)methyl)- 6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

405.0 249 1-((2-methoxypyridin-3- yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

402.2 250 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(trifluoromethyl)-1,3,4- oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

431.1 251 2-(3-((6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridin-1-yl)methyl)-1,2,4-oxadiazol-5- yl)propan-2-ol

421.2 252 1-((5-ethyl-1,3,4-oxadiazol-2- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

391.2 253 1-((5-cyclopropyl-1,3,4-oxadiazol- 2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

403.2 254 1-((5-(methoxymethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

407.2 255 (1-((2-chloro-6-methylpyridin-4- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2-yl)methanol

433.9 256 (1-(4-fluorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)methanol

405.1 257 (1-(4-chlorobenzyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-1H- imidazo[4,5-b]pyridin-2- yl)methanol

421.2 258 1-((1,4-dimethyl-1H-pyrazol-5- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

389.3 259 1-((1-(difluoromethyl)-1H- pyrazol-4-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

411.2 260 1-((2,5-dimethyl-1,3-oxazol-4- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

390.2 261 1-((2,4-dimethyl-1,3-oxazol-5- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

390.2 262 1-((1,4-dimethyl-1H-pyrazol-3- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

389.2 263 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((4-methylpyrimidin-2-yl)methyl)- 1H-imidazo[4,5-b]pyridine

387.2 264 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((4-(trifluoromethyl)pyrimidin-2- yl)methyl)-1H-imidazo[4,5- b]pyridine

441.1 265 1-((5-isobutyl-1,3,4-oxadiazol-2- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

419.2 266 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((4-methyl)-6- (trifluoromethyl)pyrimidin-2- yl)methyl)-1H-imidazo[4,5-b]pyridine

455.2 267 1-((5-isopropyl-1,3,4-oxadiazol-2- yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

405.2 268 1-((5-cyclobutyl-1,3,4-oxadiazol- 2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

417.2 269 1-((5-(3,3-difluorocyclobutyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

453.2 270 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(1-methylcyclopropyl)-1,3,4- oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

417.2 271 1-((5-(1,1-difluoropropyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

441.2 272 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(1,1,2,2-tetrafluoroethyl)- 1,3,4-oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

461.0 273 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-1,2-dimethyl-1H-imidazo[4,5-b]pyridine

295.1 274 1-((5-(1,1-difluoroethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

427.1 275 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(3-methyloxetan-3-yl)-1,3,4- oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

433.2 276 1-((5-(2,2-difluorocyclopropyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

439.2 277 1-((5-(2-fluoropropan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

423.2 278 1-((6-methoxypyrazin-2- yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

403.2 279 1-((5-(1-fluoroethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

409.2 280 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiadiazol-4-ylmethyl)-1H- imidazo[4,5-b]pyridine

379.2 281 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((5-(2,2,2-trifluoroethyl)-1,3,4- oxadiazol-2-yl)methyl)-1H-imidazo[4,5-b]pyridine

445.2 282 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-(1,2,3-thiadiazol-5-ylmethyl)-1H- imidazo[4,5-b]pyridine

379.2 283 1-((5-(1-fluorocyclopropyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4- methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H- imidazo[4,5-b]pyridine

421.2 284 1-((5-(1-fluorocyclobutyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

435.2 285 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((4-methyl-1,2,3-thiadiazol-5- yl)methyl)-1H-imidazo[4,5- b]pyridine

393.2 286 1-((5-((1R)-1-fluoroethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

409.3 287 1-((5-((1S)-1-fluoroethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

409.3 288 1-((5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[1,2-b]pyridazin-5- yl)-2-methyl-1H-imidazo[4,5-b]pyridine

410.0 289 1-((5-(difluoromethyl)-1,3,4- thiadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine

429.2 290 6-(4-methoxypyrrolo[2,1- f][1,2,4]triazin-5-yl)-2-methyl-1-((6-methylpyrazin-2-yl)methyl- 1H-imidazo[4,5-b]pyridine

387.3

Preparation Example 1

A medicament containing the present invention compound as an activeingredient can be produced in accordance with, for example, thefollowing formulation.

Equation 1 1. capsule (1) compound obtained in Example 1 40 mg (2)lactose 70 mg (3) microcrystalline cellulose  9 mg (4) magnesiumstearate  1 mg one capsule 120 mg 

Components (1), (2) and (3), and one-half of component (4) are mixed,and then granulated. The remainder of component (4) is added thereto,and the whole of the mixture is encapsulated in a gelatin capsule.

Equation 2 2. tablet (1) compound obtained in Example 1 40 mg (2)lactose 58 mg (3) corn starch 18 mg (4) microcrystalline cellulose 3.5mg  (5) magnesium stearate 0.5 mg  one tablet 120 mg 

Components (1), (2) and (3), two-thirds of component (4), and one-halfof component (5) are mixed, and then granulated. The remainders ofcomponents (4) and (5) are added to the resulting granule, and themixture is press-molded into a tablet.

Preparation Example 2

50 mg of the compound obtained in each of examples is dissolved in 50 mLof injection distilled water in Japanese Pharmacopoeia, and injectiondistilled water in Japanese Pharmacopoeia Japanese is added so that thevolume of the solution is 100 mL. The solution is filtered under sterileconditions, and 1 mL of the solution is then taken, filled into aninjection vial under sterile conditions, freeze-dried, and hermeticallysealed.

Test Example 1 (Test Method: Measurement of CLK2 Inhibitory Activity)

A test compound dissolved in DMSO was added to a reaction solution (50mM HEPES (pH: 7.5), 10 mM MgCl₂, 1 mM EGTA, 2 mM DTT, 0.01% Tween 20,0.01% BSA) containing a CLK2 enzyme (Thermo Fisher Scientific) and anULight-labeled MBP peptide (PerkinElmer), and the mixture was thenreacted at room temperature for 10 minutes. An ATP solution was added toa final concentration of 1 mM to initiate an enzyme reaction, and thereaction was carried out at room temperature for 60 minutes. Aeuropium-labeled anti-phosphorylated MBP antibody (PerkinElmer) and aLANCE Detection buffer (PerkinElmer) containing EDTA with a finalconcentration of 20 mM were added to stop the reaction, the mixture wasleft standing for 60 minutes, and the time-resolved fluorescence value(excitation 320 nm, and emission 615 nm and 665 nm) was measured byEnvision (PerkinElmer). The inhibition ratio (%) of CLK2 by the testcompound was calculated in accordance with the following expression.

Inhibition ratio (%)=(1−(count of testcompound−blank)+(control−blank))×100

The count of the CLK2 enzyme reaction solution without addition of thecompound was described as a control, and the count without addition ofthe compound and addition of the CLK2 enzyme was described as a blank.The concentration at which the inhibition ratio was 50% was defined asan IC₅₀ value.

The test results are shown in Table 2.

TABLE 2 CLK2 activity inhibition ratio at Example No. compoundconcentration of 1 μM (ATP 1 mM) 7 100% 102 100% 105 100% 110 100% 160100% 161 100% 175 100% 176 100% 186  99% 193 100% 214  99% 215 100% 229100% 242 100% 274 100% 277 100% 283 100% 286 100%

These results showed that the present invention compound had CLK2inhibitory activity.

Test Example 2 (Measurement of Growth Inhibitory Activity Using HCT116Cells)

HCT 116 cells (ATCC) were seeded in a 384-well plate at a density of6×10² cells/well, and cultured overnight in a cell culture mediumMcCoy's 5A (Thermo Fisher Scientific) containing 10% FBS (fetal bovineserum) and 1% penicillin/streptomycin. The dissolved test compound wasadded in the cell medium, and the cell medium was left standing in a CO₂incubator (37° C.) for 3 days. A Cell Titer-Glo solution (PromegaCorporation) was added, the mixture was stirred at room temperature for10 minutes, and the emission value was measured by Envision(PerkinElmer). The inhibition ratio (%) of HCT116 cell growth by thetest compound was calculated in accordance with the followingexpression.

Inhibition ratio (%)=(1−(count of testcompound−blank)+(control−blank))×100

The count of the HCT116 cell suspension without addition of the compoundwas described as a control, and the count without addition of thecompound and addition of HCT116 cells was described as a blank. Theconcentration at which the inhibition ratio was 50% was defined as anIC₅₀ value.

The test results are shown in Table 3.

TABLE 3 Cell growth inhibition ratio at Example No. compoundconcentration of 1 μM 7 92% 102 95% 105 96% 110 92% 160 98% 161 97% 17591% 176 85% 186 96% 193 98% 214 96% 215 95% 229 97% 242 94% 274 93% 27795% 283 96% 286 95%

These results showed that the present invention compound inhibitedgrowth of colon adenocarcinoma cells.

In Vitro CLK2 Phosphorylation Inhibitory Action and p53 ActivationAction in Human Colon Adenocarcinoma Cells HCT 116

1000 μl (8,0000 cells/well) of a cell suspension of human colonadenocarcinoma cells HCT116 (purchased from ATCC) was seeded in a12-well plate, and cultured at 37° C. for 2 days in a 5% CO₂ gasincubator. The test compound solution was added to a final concentrationof 300 nM, and the mixture was cultured for 16 hours. The plate waswashed with PBS, a protein extract (10% glycerol, 1% sodium dodecylsulfate, 62.5 mM Tris-HCl (pH: 7.5)) was then added to dissolve thecells, and the solution was treated at 95° C. for 5 minutes. Thereafter,the amount of protein was determined using BCA Protein Assay Kit (ThermoFisher Scientific).

The amount of the protein in each sample was adjusted, SDS-PAGE was thenperformed, and the protein was transferred to a PVDF membrane using aniBlot (registered trademark) gel transfer system (Invitrogen). Blockingwas performed using StartingBlock T20 (PBS) Blocking Buffer (ThermoFisher Scientific), and the sample was reacted at 4° C. overnight withanti-phosphorylation CLK2 (Ser98), an anti-MDM4 antibody (BethylLaboratories, Inc., A300-287A), an anti-p53 antibody (Santa Cruz, Inc.,sc-126) and anti-p21 antibody (Santa Cruz, Inc., sc-6246) each diluted1000 times with Can Get Signal Immunoreaction Enhancer Solution 1(TOYOBO CO., LTD.). The membrane was washed with Tris-buffered saline(Bio-Rad Laboratories, Inc.) containing 0.05% of Tween 20 (Bio-RadLaboratories, Inc.), and the sample was then reacted at room temperaturefor 1 hour with a HRP-labeled rabbit IgG polyclonal antibody (NA 9340from GE Healthcare) diluted 5000 times with Can Get SignalImmunoreaction Enhancer Solution 2 (TOYOBO CO., LTD.). The membrane waswashed in the same procedure as described above, a phosphorylated CLK2protein, a MDM4 protein, a p53 protein and a p21 protein each labeledwith an antibody were then made chemiluminescent using ImmunoStar ZETA(Wako Pure Chemical Industries, Ltd.), and luminescence was detectedwith LAS-3000 Image Analyzer (Fujifilm Corporation). The luminescenceintensity was determined using Multi Gauge Ver. 3.1 (FujifilmCorporation), and quantified.

The CLK2 phosphorylation inhibitory activity of the test compound iscalculated as a phosphorylated CLK2 residual ratio (%) in accordancewith the following expression, and shown in Table 4.

Residual ratio (%)=(phosphorylated CLK2 signal of testcompound÷phosphorylated CLK2 signal of control group)×100

TABLE 4 Test compound Concentration Residual ratio (Example No.) (nM)(%) 286 300 71.4

The MDM4 inhibitory activity of the test compound is calculated as aresidual ratio (%) in accordance with the following expression, andshown in the table.

Residual ratio (%)=(MDM4 signal of test compound÷MDM4 signal of controlgroup)×100

TABLE 5 Test compound Concentration Residual ratio (Example No.) (nM)(%) 286 300 43.6

The p53 induction activity of the test compound is calculated as anincrease ratio (%) in accordance with the following expression, andshown in Table 5.

Increase ratio (%)=(p53 signal of test compound÷p53 signal of controlgroup))×100

TABLE 6 Test compound Concentration Increase ratio (Example No.) (nM)(%) 286 300 620.7

The p21 induction activity of the test compound is calculated as anincrease ratio (%) in accordance with the following expression, andshown in Table 6.

Increase ratio (%)=(p21 signal of test compound÷p21 signal of controlgroup))×100

TABLE 7 Test compound Concentration Increase ratio (Example No.) (nM)(%) 286 300 556.4

These results showed that the present invention compound inhibitedphosphorylation of CLK2, decreased the amount of the MDM4 protein, andincreased the amounts of the p53 and p21 proteins in colonadenocarcinoma cells.

In Vitro MDM4 Alternative Splicing Ratio in Human Colon AdenocarcinomaCell HCT 116

1000 μl (20,0000 cells/well) of a cell suspension of human colonadenocarcinoma cells HCT116 (purchased from ATCC) was seeded in a12-well plate, and cultured at 37° C. for 1 day in a 5% CO₂ gasincubator. The test compound solution was added to a final concentrationof 300 nM, and the mixture was cultured for 6 hours. The plate waswashed with PBS, the cells were then dissolved using RNeasy Mini Kit(QIAGEN), and RNA was extracted. Using cDNA after reverse transcriptionreaction, the number of copies of the MDM4 transcription productcontaining exon 6 (MDM4 FL) and the MDM4 transcription product in whichexon 6 was skipped (MDM4 S) was measured by quantitative PCR. Primerswith the following sequences were used for the measurement.

Primers with the following sequences were used for the measurement.

MDM4 FL (Hs 00967241_m1, Thermo Fisher Scientific) MDM4 S (Forward primer, GACCCAAGCCCTCTCTATGATATG;Reverse primer, TCTGTAGTTCTTTTTCTGGAAGTGGAA;probe, TACTACAGCAAAGTGCAGAGG, Thermo Fisher Scientific)

The following oligos were used for preparing a calibration curve.

MDM4 FL Oligo (CCCTCTCTATGATATGCTAAGAAAGAATCTTGTCACTTTAGCCACTGCTACTACAGATGCTGCTCAGACTCTCGCTCTCGCACAGGATCACAGTATGGA, Thermo Fisher Scientific); MDM4 S Oligo(TGAAAGACCCAAGCCCTCTCTATGATATGCTAAGAAAGAATCTTGTCACTTTAGCCACTGCTACTACAGCAAAGTGCAGAGGAAAGTTCCACTTCCAGAAAAAGAACTACAGAAGACG, Thermo Fisher Scientific)

A change in MDM4 alternative splicing ratio (PSI) is calculated inaccordance with the following expression, and changes caused by the testcompound are shown in Table 8.

PSI=(number of copies of MDM4 FL−(number of copies of MDM4 FL+number ofcopies of MDM4 S))×100

TABLE 8 Test compound (Example No.) PSI Control (DMSO) 75.75 286 45.81

These results showed that the present invention compound increased theratio of transcription product (MDM4 S) in which exon 6 of MDM4 wasskipped in colon adenocarcinoma cells.

In Vitro MYC-Induced Human Malignant Melanoma Cell SK-MEL-28 GrowthInhibitory Action

Human MYC cDNA was inserted downstream of the TRE of a lentiviral vector(modified pTRIPZ: GE Healthcare) having a tetracycline responsivesequence (TRE) in the promoter region. The produced virus was infectedwith human malignant melanoma cells SK-MEL-28 (purchased from ATCC) toestablish SK-MEL-28 cells (SK-MEL-28-MYC) inducing expression of MYC inthe presence of doxycycline (Takara Bio Inc.) which is a tetracyclinederivative. SK-MEL-28 cells (SK-MEL-28—Control) having an empty vectorwith only modified pTRIPZ were also established. 20 μL/well of 2.5 μg/mLdoxycycline-containing medium was added to a 96-well plate, and 80μl/well (1,000 cells/well) of a cell suspension was added, and culturedat 37° C. for 2 days in a 5% CO₂ gas incubator. Thereafter, 100 μl of a250 nM test compound solution was added (final concentration: 125 nM),and the mixture was further cultured for 3 days. 50 μl/well of aCellTiter-Glo™ Luminescent Cell Viability Assay reagent (PromegaCorporation) was added to a 96-well plate, the amount of luminescencewas measured by a luminometer, and the amount of remaining ATP wasdetermined as a cell amount. The inhibition ratio (%) of cell growth bythe test compound was calculated in accordance with the followingexpression.

Inhibition ratio (%)=(1−(amount of luminescence of testcompound)+(amount of luminescence of control group))×100

The inhibition ratios of the test compounds are shown in Table 9.

TABLE 9 Inhibition ratio (%) by compound (125 nM) of Example 286 CellDoxycycline (−) Doxycycline (+) SK-MEL-28-Control 34.4 35.7SK-MEL-28-MYC 24.7 69.3

These results showed that the present invention compound had a strongergrowth inhibitory action on a cancer cell line in which MYC was inducedthan on a cancer cell line in which MYC was not induced.

Antitumor Action on Tumor-Bearing Model Derived from Patient with AcuteMyeloid Leukemia Having SF3B1 Gene Mutation

A tumor derived from a myelogenous leukemia patient having a mutation inthe SF3B1 gene was subcutaneously transplanted into mice to establish aclinical tumor model capable of undergoing in vivo passage. A fragmentof the tumor was subcutaneously transplanted into a six-week-old NOGfemale mice (CLEA Japan, Inc.) with a trocar, the tumor diameter of thedeveloped tumor was measured 52 days after the transplantation, and thetumor volume was calculated in accordance with the following expression.

Tumor volume=long diameter×short diameter×short diameter×(½)

Individuals with a tumor developed to a tumor volume of about 200 mm³were selected, and six mice per group were used for the experiment. A0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd.)suspension of the test compound was orally administered at a dose of 50mg/kg (10 mL/kg) twice a day on 2 days per week for 2 weeks. The tumorvolume was chronologically measured on the day before the start ofadministration and every 3 to 4 days, the tumor diameter was finallymeasured on the day after completion of administration for 14 days, andthe tumor volume was calculated.

The tumor growth in the test compound administration group with respectto the control administration group was calculated as a T/C value inaccordance with the following expression.

T/C=(tumor volume after completion of administration in test compoundadministration group−tumor volume on day before start of administrationin test compound administration group)/(tumor volume after completion ofadministration in control administration group−tumor volume before startof administration in control administration group))×100

The T/C values of the test compound are shown in Table 10.

TABLE 10 Test compound (Example No.) Dose (mg/kg) T/C (%) 286 50 −30.4

These results showed that the present invention compound had anantitumor action in a tumor model derived from an acute myeloid leukemiapatient having a mutation in the SF3B1 gene.

The present application is based on JP-A-2016-091717 filed in Japan, thedisclosure of which is incorporated herein in its entirety.

INDUS TRIAL APPLICABILITY

The present invention compound has a CLK inhibitory action. Therefore,the present invention compound can be used as a CLK inhibitor, and isuseful as a prophylactic or therapeutic agent for CLK-related diseasesincluding cancer.

1-12. (canceled)
 13. A method for inhibiting CLK in a mammal, comprisingadministering to the mammal an effective amount of a compoundrepresented by the formula (I), or hydrate or salt thereof,

wherein: R¹ represents a substituent or a hydrogen atom; R² representsan optionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; R⁶ and R⁷ each independently represent a hydrogenatom, a halogen atom or an optionally substituted hydrocarbon group; andring A represents a bicyclic aromatic heterocycle selected from thefollowing formulas (1), (2), (3), (4) and (5):

wherein Xs each independently represent N or C(R⁵); and R³, R⁴ and R⁵each independently represent a hydrogen atom or a substituent.
 14. Amethod for preventing or treating at least one cancer selected from thegroup consisting of colon cancer, melanoma, acute myeloid leukemia, lungcancer, breast cancer, pancreatic cancer, myelodysplastic syndrome andovarian cancer in a mammal, the method comprising administering to themammal an effective amount of a compound represented by the formula (I),or a hydrate or salt thereof,

wherein: R¹ represents a substituent or a hydrogen atom; R² representsan optionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; R⁶ and R⁷ each independently represent a hydrogenatom, a halogen atom or an optionally substituted hydrocarbon group; andring A represents a bicyclic aromatic heterocycle selected from thefollowing formulas (1), (2), (3), (4) and (5):

wherein Xs each independently represent N or C(R⁵); and R³, R⁴ and R⁵each independently represent a hydrogen atom or a substituent. 15-16.(canceled)
 17. The method according to claim 13, wherein the compoundrepresented by the formula (I), or hydrate or salt thereof is6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine.18. The method according to claim 13, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.19. The method according to claim 13, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-(1,1-difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.20. The method according to claim 13, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.21. The method according to claim 14, wherein the compound representedby the formula (I), or hydrate or salt thereof is6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-1H-imidazo[4,5-b]pyridine.22. The method according to claim 14, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.23. The method according to claim 14, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-(1,1-difluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.24. The method according to claim 14, wherein the compound representedby the formula (I), or hydrate or salt thereof is1-((5-((1R)-1-fluoroethyl)-1,3,4-oxadiazol-2-yl)methyl)-6-(4-methoxypyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methyl-1H-imidazo[4,5-b]pyridine.